IE44942B1 - Novel piperazine and piperidine derivatives - Google Patents
Novel piperazine and piperidine derivativesInfo
- Publication number
- IE44942B1 IE44942B1 IE699/77A IE69977A IE44942B1 IE 44942 B1 IE44942 B1 IE 44942B1 IE 699/77 A IE699/77 A IE 699/77A IE 69977 A IE69977 A IE 69977A IE 44942 B1 IE44942 B1 IE 44942B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- parts
- group
- compound
- lower alkyl
- Prior art date
Links
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 150000003053 piperidines Chemical class 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 150000002148 esters Chemical class 0.000 claims abstract description 35
- 239000002253 acid Substances 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 73
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 37
- -1 or a lower alkyi Chemical group 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 6
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical group [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
- 230000000911 decarboxylating effect Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 150000002829 nitrogen Chemical class 0.000 claims 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- CRLDYDFRKDTPNY-UHFFFAOYSA-N 1-(4-chlorobutyl)benzimidazole Chemical compound C1=CC=C2N(CCCCCl)C=NC2=C1 CRLDYDFRKDTPNY-UHFFFAOYSA-N 0.000 claims 1
- GUMPYDGUYXOYML-UHFFFAOYSA-N 3-(3-chloropropyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCl)C2=C1 GUMPYDGUYXOYML-UHFFFAOYSA-N 0.000 claims 1
- HLJJJPMNIFNKCI-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-benzimidazol-2-one Chemical compound C1=CC=C2NC(=O)N(CCCCCl)C2=C1 HLJJJPMNIFNKCI-UHFFFAOYSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 125000005059 halophenyl group Chemical group 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 230000002804 anti-anaphylactic effect Effects 0.000 abstract description 6
- 150000007513 acids Chemical class 0.000 abstract description 5
- 239000000739 antihistaminic agent Substances 0.000 abstract description 4
- 229910052740 iodine Inorganic materials 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 229940125715 antihistaminic agent Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 35
- 239000000543 intermediate Substances 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 19
- 229960001701 chloroform Drugs 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000002585 base Substances 0.000 description 17
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 15
- 238000010992 reflux Methods 0.000 description 14
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 10
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 229960001340 histamine Drugs 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 230000001387 anti-histamine Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 239000012258 stirred mixture Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 125000003396 thiol group Chemical class [H]S* 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 241000700198 Cavia Species 0.000 description 3
- 108010058846 Ovalbumin Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 229960004217 benzyl alcohol Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 229940092253 ovalbumin Drugs 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 150000004885 piperazines Chemical class 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- HXROHDYGZFFVMO-UHFFFAOYSA-N 4-benzhydryloxypiperidine;hydrochloride Chemical compound [Cl-].C1C[NH2+]CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 HXROHDYGZFFVMO-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 210000000548 hind-foot Anatomy 0.000 description 2
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- WOFRVOOYNJVVIK-UHFFFAOYSA-N n-(3-chloropropyl)-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC=CC=C1NCCCCl WOFRVOOYNJVVIK-UHFFFAOYSA-N 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Inorganic materials [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- QSWKFJLPMWWZJE-UHFFFAOYSA-N (4-chlorophenyl)-(2-fluorophenyl)methanone Chemical compound FC1=CC=CC=C1C(=O)C1=CC=C(Cl)C=C1 QSWKFJLPMWWZJE-UHFFFAOYSA-N 0.000 description 1
- WTRWBYGUMQEFFI-UHFFFAOYSA-N (4-fluorophenyl)(pyridin-4-yl)methanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC=NC=C1 WTRWBYGUMQEFFI-UHFFFAOYSA-N 0.000 description 1
- FVUJPXXDENYILK-WITUOYQCSA-N (4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[2-[[(2S)-1-[[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]propanoyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)Cc1cnc[nH]1)[C@@H](C)O)[C@@H](C)O)C(=O)N[C@@H](C(C)C)C(N)=O FVUJPXXDENYILK-WITUOYQCSA-N 0.000 description 1
- AXDCNQMJSHRGHN-UHFFFAOYSA-N (methoxycarbonylamino)methyl methanimidate Chemical compound COC(=O)NCOC=N AXDCNQMJSHRGHN-UHFFFAOYSA-N 0.000 description 1
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical class NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- CUJPFPXNDSIBPG-UHFFFAOYSA-N 1,3-propanediyl Chemical group [CH2]C[CH2] CUJPFPXNDSIBPG-UHFFFAOYSA-N 0.000 description 1
- OMIVCRYZSXDGAB-UHFFFAOYSA-N 1,4-butanediyl Chemical group [CH2]CC[CH2] OMIVCRYZSXDGAB-UHFFFAOYSA-N 0.000 description 1
- MKZOYCWVYJRSAQ-UHFFFAOYSA-N 1-(3-chloropropyl)-3-prop-1-en-2-ylbenzimidazol-2-one Chemical compound C1=CC=C2N(CCCCl)C(=O)N(C(=C)C)C2=C1 MKZOYCWVYJRSAQ-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-UCVXFZOQSA-N 1-[(2s,3s,4s,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O[C@H]1[C@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UCVXFZOQSA-N 0.000 description 1
- LHASLBSEALHFGO-ASZAQJJISA-N 1-[(4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-[[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]pyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO)OC1N1C(=O)NC(=O)C(CO[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=C1 LHASLBSEALHFGO-ASZAQJJISA-N 0.000 description 1
- HXDAZUSPEXGQSS-UHFFFAOYSA-N 1-[bromo-(4-fluorophenyl)methyl]-4-fluorobenzene Chemical compound C1=CC(F)=CC=C1C(Br)C1=CC=C(F)C=C1 HXDAZUSPEXGQSS-UHFFFAOYSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- 125000006018 1-methyl-ethenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- QLWOUBCORTYSPP-UHFFFAOYSA-N 1h-imidazol-1-ium;hydroxide Chemical compound O.C1=CNC=N1 QLWOUBCORTYSPP-UHFFFAOYSA-N 0.000 description 1
- CEOCVKWBUWKBKA-UHFFFAOYSA-N 2,4-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1Cl CEOCVKWBUWKBKA-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- GZNFEOAHZBEZLE-UHFFFAOYSA-N 3-(2-aminoanilino)propan-1-ol Chemical compound NC1=CC=CC=C1NCCCO GZNFEOAHZBEZLE-UHFFFAOYSA-N 0.000 description 1
- DEGLZHLLRWQEKQ-UHFFFAOYSA-N 3-(2-methylsulfanylbenzimidazol-1-yl)propan-1-ol Chemical compound C1=CC=C2N(CCCO)C(SC)=NC2=C1 DEGLZHLLRWQEKQ-UHFFFAOYSA-N 0.000 description 1
- JPDLWRGYOGEWID-UHFFFAOYSA-N 3-(2-nitroanilino)propan-1-ol Chemical compound OCCCNC1=CC=CC=C1[N+]([O-])=O JPDLWRGYOGEWID-UHFFFAOYSA-N 0.000 description 1
- RNQZLQWESDIMLF-UHFFFAOYSA-N 3-(3-hydroxypropyl)-1h-benzimidazole-2-thione Chemical compound C1=CC=C2N(CCCO)C(S)=NC2=C1 RNQZLQWESDIMLF-UHFFFAOYSA-N 0.000 description 1
- DXYQOUIUEIVIQH-UHFFFAOYSA-N 3-(5-chloro-2-cyclohexylbenzimidazol-1-yl)propan-1-ol Chemical compound N=1C2=CC(Cl)=CC=C2N(CCCO)C=1C1CCCCC1 DXYQOUIUEIVIQH-UHFFFAOYSA-N 0.000 description 1
- IEFAGJXJEZEQHU-UHFFFAOYSA-N 3-(5-chloro-2-ethylbenzimidazol-1-yl)propan-1-ol Chemical compound ClC1=CC=C2N(CCCO)C(CC)=NC2=C1 IEFAGJXJEZEQHU-UHFFFAOYSA-N 0.000 description 1
- XKPCFLQOHAXRQI-UHFFFAOYSA-N 3-(5-chloro-2-methylbenzimidazol-1-yl)propan-1-ol Chemical compound ClC1=CC=C2N(CCCO)C(C)=NC2=C1 XKPCFLQOHAXRQI-UHFFFAOYSA-N 0.000 description 1
- MCUSVJQHGDUXFV-UHFFFAOYSA-N 3-(benzimidazol-1-yl)propan-1-ol Chemical compound C1=CC=C2N(CCCO)C=NC2=C1 MCUSVJQHGDUXFV-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- ZBBJTKRHIIHRJX-UHFFFAOYSA-N 3-piperazin-1-ylpropan-1-amine;hydrochloride Chemical compound Cl.NCCCN1CCNCC1 ZBBJTKRHIIHRJX-UHFFFAOYSA-N 0.000 description 1
- OEIUPGGSXIKZBB-UHFFFAOYSA-N 4,5-dichloro-n-(3-chloropropyl)-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC(Cl)=C(Cl)C=C1NCCCCl OEIUPGGSXIKZBB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- SEQLNTGSELNDHC-UHFFFAOYSA-N 4-(benzimidazol-1-yl)butan-1-ol Chemical compound C1=CC=C2N(CCCCO)C=NC2=C1 SEQLNTGSELNDHC-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 1
- 101100025412 Arabidopsis thaliana XI-A gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical class NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 241000490229 Eucephalus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- WZELXJBMMZFDDU-UHFFFAOYSA-N Imidazol-2-one Chemical compound O=C1N=CC=N1 WZELXJBMMZFDDU-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 101100114416 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) con-10 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QMTFICBPEVWVIE-UHFFFAOYSA-N carbonyl dichloride;urea Chemical compound NC(N)=O.ClC(Cl)=O QMTFICBPEVWVIE-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- ONPIGXOVMNUZEY-UHFFFAOYSA-N ethyl 4-benzhydryloxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 ONPIGXOVMNUZEY-UHFFFAOYSA-N 0.000 description 1
- QABJNOSERNVHDY-UHFFFAOYSA-N ethyl 4-hydroxypiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(O)CC1 QABJNOSERNVHDY-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 210000002683 foot Anatomy 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UUBJKHVFGWGJKX-UHFFFAOYSA-N hydrate tetrahydrochloride Chemical compound O.Cl.Cl.Cl.Cl UUBJKHVFGWGJKX-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229940079826 hydrogen sulfite Drugs 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 238000007031 hydroxymethylation reaction Methods 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000004694 iodide salts Chemical group 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 235000013675 iodine Nutrition 0.000 description 1
- 229960002358 iodine Drugs 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 229940101209 mercuric oxide Drugs 0.000 description 1
- 229910052751 metal Chemical class 0.000 description 1
- 239000002184 metal Chemical class 0.000 description 1
- 229910001511 metal iodide Inorganic materials 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- QRKVRHZNLKTPGF-UHFFFAOYSA-N phosphorus pentabromide Chemical compound BrP(Br)(Br)(Br)Br QRKVRHZNLKTPGF-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- DKORSYDQYFVQNS-UHFFFAOYSA-N propyl methanesulfonate Chemical compound CCCOS(C)(=O)=O DKORSYDQYFVQNS-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 108700043117 vasectrin I Proteins 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic 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
-
- 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
-
- 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
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- 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
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/26—Oxygen 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
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/28—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
- C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Piperazine and piperidine derivatives of the general formula I in which the substituents are defined in claim 1, as well as their salts with acids, are obtained by reacting a corresponding reactive ester with a compound of the general formula III and, where appropriate, converting the products which have been prepared into the corresponding salts using acids. The compounds of the general formula I, as well as their pharmacologically tolerated salts with acids, exhibit, for example, strong effects as antianaphylactics and antihistamines and are consequently useful active compounds in human and veterinary medicine.
Description
The present invention relates to piperazine and piperidine derivatives.
A number of 1- £ (heterocyclyl) alkyl_7piperazines and a number of 1-substituted 4-(diarylmethyl)- piperazine and 4-(diarylmethoxy)piperidine derivatives having pharmacological properties are described in the prior art. Such compounds are described in the following references: United States Patents Nos. 3,362,956, 3,472.854, 3,369,022, 2,882,271 and 3,956,328 and C.A., 64, 3499e (1966).
The compounds of this invention differ from the prior art compounds essentially by the nature of the E-C^Hg^ group, present in the 1-position of the piperazine or piperidine group, and/or by the nature of the diarylmethyl or diarylmethoxy group present in the 4-position of said piperazine or piperidine group.
Accordingly, the present invention provides piperazine and piperidine derivatives which may structurally be represented by the formula: (I) - 2 4 4s 4s and the pharmaceutically acceptable acid addition salts thereof, wherein: 2 Ar and Ar are each independently a pyridinyl phenyl or substituted phenyl group, the substituted phenyl group having 1 or 2 substituents which are each independently a halogen atom, a lower alkyl, lower alkyloxy, trifluoromethyl or nitro group; m is 0 or 1; A is a N- or CH- group, provided that when A is N- then m is 0 and when A is CH- then m is 1; n is an integer of from 2 to 6 inclusive, provided that when cnH2n represents a branched alkylene chain, then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidine or piperazine nitrogen atom; and B is: a) a group having 'the formula Λ Λ® wherein: 2 R and R are each independently a hydrogen or halogen atom, or a lower alkyl or trifluoromethyl group; and Y is an oxygen or sulfur atom or a possibly substituted ·%. nitrogen atom of the formula ^N-L wherein L is a hydrogen atom or a lower alkyl, lower alkylcarbonyl, lower alkyloxycarbony 1- lower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or alkenyl group; or b) a group having the formula M wherein: 2 R and R are as above defined; and M is a hydrogen atom or a lower alkyl, phenyl, phenylmethy1, mercapto, lower alkylthio, amino, lower alkylcarbonylamino, lower alkyloxycarbonylamino or Cycloalkyl group having from 3 to 6 carbon atoms. ΖΛ . y By the term lower alkyl as used herein is meant straight and branched chain alkyl groups having from 1 to 6 carbon atoms such as, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl and hexyl; by the term lower alkenyl as used herein is meant straight and branched chain alkenyl groups having from 2 to 6 carbon atoms such as, etheny.l, 1-methylethenyl, 1propenyl, 2-propenyl, 2-butenyl, l-methyl-2-butenyl, 2pentenyl and 2-hexenyl; by the term cycloalkyl as used herein is meant cyclic hydrocarbon groups having from 3 to 6 carbon atoms such as, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the expression CnH2 refers to straight and branched chain alkylene chains having from 2 to 6 carbon atoms and having at least 2 carbon atoms in the linear portion of the chain linking the Bgroup with the piperidine or piperazine nitrogen, such as, 1,2-ethanediyl, 1,3-propanediyl, 2-methyl-l,3propanediyl, 1,4-butanediyl, 2-methyl-l,4-butanediyl, 1,5-pentanediyl and 1,6-hexanediyl; and by the term halogen is meant halogens of atomic weight less than 127, i.e. fluorine, chlorine, bromine and iodine, The compounds of formula (I), except those wherein B is a 2-amino-IH-benzimidazol-l-yl group, may conveniently be .prepared by reacting an appropriate reactive ester of formula (II) wherein n is as previously defined, B is as previously defined except a 2-amino-lHbenzimidazol-l-yl group of the formula; -510 NH, I 2 n^c'nR· 2 wherein R and R are as previously defined, and W is an appropriate reactive ester function derived from the corresponding alcohol such as, halogen, methanesulfonyl or 4-methyIbenzenesulfonyl, with an appropriate piperdine of piperazine derivative of formula (III) wherein A, m, Ar1 2 and Ar are as previously defined; B-C H-W n 2n (II) Hl/ \_-(0) -CH m (III) • Ar Ar (I) This condensation reaction is preferably carried out in an appropriate reaction-inert organic solvent such as, a lower alkanol, e.g., methanol, ethanol, propanol or butanol; an aromatic hydrocarbon e.g., benzene, methylbenzene or dimethylbenzene; an ether, e.g., 1,4-dioxane or l,l'-oxybispropane; a ketone, e.g., 4-methy1-2-pentanone; N-N-dimethylformamide or nitrobenzene. The addition of an appropriate base such as, an alkali metal or earth alkali metal carbonate or hydrogen carbonate, may be utilized to pick up the acid which is liberated during the course of the reaction. A small amount of an appropriate metal iodide, e.g., sodium or potassium iodide may be added as a reaction promoter. t,· - 6 44 3 4 2 Somewhat elevated temperatures are appropriate to enhance the rate of the reaction ahd preferably the reaction is carried out at the reflux temperature of the reaction mixture.
In this and following· preparations, the reaction products are separated from the reaction mixture and, if , necessary, further purified Using methods generally known in the art.
The compounds of formula (I) wherein B stands, for a 2-amino-lH-benzimidazol-1-yl radical, (I-a), are easily prepared starting from the corresponding compounds (I) wherein B is a 2-^ower alkyloxycarbonylamino)lH-benzimidazol-1-yl radical, (I-b), by'decar boxylating the latter under hydrolytic conditions, for example, by acid hydrolysis using an appropriate strong acid, such as hydrochloric, hydrobromic or sulfuric acid, or by alkaline hydrolysis using an appropriate strong base SUCh as, sodium or potassium hydroxide. ijJH-COQ(lower alkyl) ^^>-CaH2a-Z~^A-( 0 )m-CS H+ or OH* 2 Ar JSHg (I-b) Ar1 , x Ar* // \Y Ε' 2ώ (I-a) -7It is to be noted that when the B-group in compounds of formula (I) or in intermediates therefor is a 2=(lower allcyloxycarbonylaminoJ-lH-benzimidazol-l-yl or a 2=(lower al3fiylcarbonylamino)"1H-benzimidazol=l-yl radical, then the groups may exist in'different tautomeric forms as is illustrated below: The tautomeric forms of compounds of formula (I) are included within the scope of this invention.
Compounds of formula (I) which may be represented W by the formula (I-c): S0:'Crt^''C/ \ a Ard 21 22 (I-c) -84 4948 1 2 therein 2 , 2 , n, A, Ar and Ar are as previouslydefined may alternatively be prepared by ring closure of an appropriate intermediate of formula (IV) with an appropriate cyclizing agent as known in the art for the preparation of 1,3-dihydro-2H-benziaidazol-2-ones starting from 1,2-benzenediamines.
Suitable cyclizing agents which may advantageously be employed include urea carbonyl dichloride and alkali metal isocyanates, and the cyclization reaction may be performed by methods generally known in the art. For example, when urea is used as the cyclizing agent the compounds (I-c) are easily obtained by stirring and heating the reactants together in the absence of any solvent.
The foregoing preparations may -be illustrated as follows. '' agent The compounds of formula (I-c) may also be prepared starting from the corresponding formula (V). p-sr -CnH2n -/~Y \_y a-(o) -ca Ar s. . 2 Ar (V) -912 i l 2 wherein R , R , n, A, m, Ar and Ar are as previously I defined and P is an appropriate protecting group, by the removal of the protecting group according to conventional procedures. Examples of such protecting groups are lower alkyloxycarbonyl and, a substituted ethenyl group of the formula: R -CH=C' ‘ i3 4 wherein R and R may represent different groups 10 but wherein R3 is preferably lower alkyl and R^ is preferably hydrogen, lower alkyl or phenyl.
When the protecting group is lower alkyloxycarbonyl, it may easily be removed by alkaline hydrolysis, and when the protecting group is a substituted ethenyl group it i3 conveniently eliminated by subjecting the appropriate intermediate (V) to acid hydrolysis. In carrying out this acid hydrolysis a wide variety of protonic acids may be employed, including mineral adids such as, hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, ahd organic acids such as, acetic, propanoic and ethanedioic acid. Further the reaction may be carried out in reaction-inert organic solvents as commonly employed in.such a type of hydrolytic reactions, e.g. lower alkanols such as, methanol, ethanol or 2-propanol.
In a procedure similar to that described for the preparation of the compounds (I-c) starting from (IV) compounds of the formula (I-d) may also be prepared -10449 4$ 9 5 2 wherein R , R, n, A, m, ArJ' and Ar are as previously defined, and is a hydrogen atom or a lower alkyl, phenyl phenylmethyl, mercapto, amino, lower alkyloxycarbonylamino or cycloalkyl group, by the reaction of (IV) with an appropriate cyclizing agent, using techniques known for preparing ΙΗ-benzimidazoles starting from 1,2-benzeneaiamines. Depending on the nature of in the compounds (I~di the following cyclizing agents may, for example, be employed.
When M is a hydrogen atom formic acid or an appropriate tri(alkyloxy)mechane may be used as a cyclizing agent.
When is a lower alkyl, phenyl, phenyImethyl or cycloalkyl group, a carboxylic acid of the formula; R5-COOH (VI) wherein R is a lower alkyl, phenyl, phenylmethyl, or cycloalkyl grouo, or a functional derivative thereof such as, an acyl halide, an ester, an amide or a nitrile derived from such acid or an iminoester of the formula; 0-(lower alkyl) HN=C / (VII) wherein R^ is as defined hereabove; fir an aldehyde of the formula: (VIII) or an addition product thereof with an alkali metal hydrogen sulfite, may be used. When the cyclizing agent is an aldehyde an appropriate oxidizing agent such as nitrobenzene, mercuric oxide, Cu(II) or Pb (II) salts or other known suitable oxidants may be added to the reaction mixture, or the aldehyde itself, when added in excess, may serve as the oxidant.
When M** is a mercapto group cyclizing agents such as carbon disulfide, thiourea, carbonothioic dichloride or ammonium thiocyanate may be used.
When M1 is an amino group, ring closure may be performed with cyanamide, or a metal salt thereof, preferably an alkali or earth alkali metal salt, or with BrCN.
When is a lower alkyloxycarbonylamino group, an appropriate lower alkyl (iminomethoxymethyl)carbamate of the formula (IX): 0 II II HgC-O-C-NH-C-0(lower alkyl); or (IX) -12a lower alkyl /flower alkoxy carbonylamino)(2°-thio)methylene/carbamate of the formula (x) (lower f OSO alkyl)-Q-$-N~C=N-ii-O-(lower alkyl) (X) wherein / is a hydrogen atom or a methyl group; or a lower alkyl carbonoisothiocyanatidate of the formula (XX) (lower alkyl)-C-C-NCS; or (XI) a lower alkyl lower alkylcarbamothioate of the formula (XII) S (lower alkyl)-ΝΗ~ΰ-Ο-(lower alkyl); or (XII) a dilower alkyl cyanimidodicarbonate of the formula (XIII) flower alkyl)-O-^gX-CN (XIII) may be used as the cyclizing agent.
The foregoing cyclisation reactions may all be performed by methods described in the literature. -13Compounds of the formula (I-e) NH~CO~(lower alkyl) CH, 0 ) -dH n 2a \__/ m AS (X=e) may alternatively be prepared by the acylation of an appropriate 2~ami»O"1H">benziiaid&zal~1-=yl derivative of formula (l*=a) following standard M=acylating procedures, e.g., by the reaction of (I-a) with an appropriate lewer alkylcarbonyl halide sr with aa anhydride derived from a lower alkylearboxylic acid.
Compounds of the formula (I-f) (I-f) f wherein a1» /, n, A, m, Ar1 and Ara are as' previously defined and iA is. a lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenylmethyl, lower alkylaminocarbonyi, hydroxymethyl or lower alkenyl group, provided that the unsaturation in. the lower alkenyl group is located Γ5 in a position other than a, may be prepared by the introduction of iA into a compound of formula (I-c) =14» 4 9 42 D-cr' (I-c) ,&χ ΑΓ* Depending on the nature of the I?- group to be introduced. the following methods may be utilized therefor.
When I1 is a ' lower alkyl, lower alkyloxycarbonyl-lower alkyl, phenylmethyl or lower alkenyl .group, in which case the symbol L1a is used therefor, the introdaction of L' into (I-c) may be performed by the a reaction of (I-c) with an appropriate reactive ester λ i of the formula D' -W, (XIV), wherein L' is as defined 9. 3. hereabove and W has the same meaning as given in the definition of the starting materials of formula (II).
The condensation of (XIV) with (I-c) may be carried out under conditions similar to those described for the condensation of the reactive esters (II) with the intermediates of formula (III).
In order to enhance the reaction rate it may be appropriate in some cases to add to the reaction mixture a small amount of an appropriate macrocyclic polyether such as, 2,3,11,12-dibenzo-l,4,7,10,13,16-hexaaxacyolooctadeca-2,11-diene as a reaction promoter.
When the lA group which is to be introduced is a lower alkyloxy carbonylethyl group, the introduction of the group may alter-15natively be performed by reacting (I-c) with a (lower alkyl) 2-propenoate of formula (XV) (lower alkyl)OOC-=GHsCaa (XV) This reaction may conveniently be carried out- in a reaction-inert organic solvent such as, ' as aromatic hydrocarbon, e.g., benzene, methylbenzene, or dimethylbenzene,- an ether, e.g., 1,1'o^bisethane, 2,2’-oxybispropane, tetrahydrofuran, or 1,4-dioxane, preferably ia the presence of an appropriate amiaiua hydroxide such as, for example, N,N,IT10 triethylbanzenemethanaainiuEs hydroxide.
Compounds of formula (I-f) wherein L1 is a carboxy-lower alkyl can easily be derived’from the corresponding low®? alkyloxysarbonyl-lower alkyl substituted compounds by hydrolyzing the latter in the . usual mannerj, e.g., with aqueous alkali, te liberate the acid from the ester.
When iA is- lower alkylcarbonyl the · group may conveniently be introduced by the reaction of (i'=c) with an appropriate acylating agent derived from the corresponding lower alkylearboxylic acid such as - a halide, preferably the chloride, or an anhydride, following standard Si-acyl&tiag procedures.
When iA is lower alkylaminocarbonyl it may be introduced by the reaction of (I-c) with an appropriate isocyanatoalkane in an appropriate reaction-inert· organic solvent Such ah,-an ether, e.g., l,l'-oxy-bisethane, 2,2'-oxybispropane or 1,4-dioxane. -16When L·1 is a hydroxymethyl group its introduction is conveniently performed by the reaction of (Σ-c) with formaldehyde in an appropriate organic solvent such as, Ν,N-dimethyIformamide.
Compounds of the formula (l-g) (i-s) 2. wherein 3, a, Ar and Ar are as previously defined may alternatively be prepared by the condensation of a piperazine derivative of formula (XVI) with an appropriate rea ctive ester of formula (XVII) wherein Ar , Ar and W are as previously diaPinpfi, under conditions similar to those described for the preparation of the compounds (I) starting from (II) and (III) . z W-CH Ar X Ai’2 ................(W) (XVI) (XVII) .1 Compounds of the formula (X-h) ,2 (X-h) are also conveniently prepared starting· from the corresponding -SH substituted analogs by standard S-alkylating procedures, e.g», by the reaction of the mercapto compound with aa appropriate halo-lower alkane in an approp· riate organic solvent such as, a lower alkanol, a.g., ethanol, propanol, 2-propanol or bgtanol.
A number of the intermediates of formula (II) are known compounds. Depending on the nature of 5 in the intermediates (XI) the following procedures may be utilized for preparing them.
Intermediates of the formula (XX-a) R H (XX-a) -184 4 S 4 8 may be prepared as follows: An appropriately substituted 2-chloror.itrobenzene of formula (XVIII) is reacted with an appropriate aminoalkanol (XIX) by refluxing the reactants together in an S appropriate reaction-inert organic solvent such as, a lower alkanol, e.g. , ethanol, propanol, 2-propanol or butanol, whereupon a / (2-nitrophenyl)amino7alkanol of formula (XX) is obtained, which in turn is subjected to a nitro-to-amine reduction, e.g., by catalytic hydrogenation using Raney-nickel catalyst. The soobtained intermediate (XXI) is then reacted with an appropriate cyclizing agent an described hereinbefore for the preparation of the compounds (I-o) starting from (IV), and the thus-obtained alcohol of formula (XXII) is subsequently converted into the desired reactive ester (II-a) by the known methods. Halides are conveniently prepared by Lhe reaction of (XXII) with an appropriate halogenating agent such as, sulfinyl chloride, sulfuryl chloride, phosphor pentachloride, phosphor pentabromide or phosphoryl chloride. When the reactive ester is an iodide, it is preferably derived from the corresponding chloride or bromide by the replacement of that halogen with iod-ine. Other reactive esters such as methanesulfonates and 4-methylbenzenesul23 fonates are obtained by the reaction of the alcohol with an appropriate sulfonyl halide such as, methanesulfonyl chloride and 4-methylbenzenesurfonyl chloride, respectively.
The foregoing reactions are more clearly illustrated in the following schematic representation. 1:3 -¾ 02U Cl 21 22 V"CnH2n=°H (XXX) (mn) Hg / Sain =$> (XX) a 2& -OEf ring closure --—----> reactive ester .........................(XX-a) formation —20— 4 9 4 2 • Alternatively the intermediates of formula (H-a) may also be prepared by: i) reacting a compound of formula (XXIII) wherein S3 and S4 are as previously defined with a haloalkanol of formula (XXIV) by conventional N-alkylating procedures to obtain an alcohol of formula (XXV); ii) converting the hydroxyl function of (XXV) into a reactive ester group in the usual manner as previously described; and iii) eliminating the substituted ethenyl group of the thus obtained (XXVI) by acid hydrolysis as described hereinbefore for the preparation of (I-c) starting from (V).
The introduction of the hydroxyalkyl chain in (XXIII) to obtain (XXIV) may also be performed by the reaction of (XXIII) with an appropriate 2-(haloalkyloxy)tetrahydro2H-pyran of formula (XXVII), yielding an intermediate of formula (XXVIII), the ether function of which is hydrolytically split open, e.g., by the treatment with an aqueous hydrochloric acid solution.
When the reactive ester (ll-a) is a halide, (II-a-1), it may alternatively be prepared by the reaction of (XXIII) with an equivalent amount of an appropriate dihaloalkane, (XXIX) in the presence of an appropriate strong base such as, for example, sodium methoxide, or following a Mackosza procedure using aqueous alkali and a quaternary ammonium catalyst, e.g., Ν,Ν,Μ-triathylbenzenemethanaminium chloride, yielding, an intermediate of formula (XXVI-a), the substituted ethenyl group of which is subsequently removed by acid hydrolysis, 'to yield the desired halide (II-a-1).
It is to .be noted that the same procedures are also applicable when the substituted ethenyl group is replaced by another appropriate that removal thereof has to be performed following, appropriate methods for the elimination of the particular group involved.
The foregoing reactions are more clearly illustrated in the following schematic representation»· -2244942 23' nfi Intermediates of the formula (Il-b) wherein , a and V are as previously defined and ΐΛ is selected from the group consisting of lower alkyl» lower alkenyl, lower ailcyLaxycarbaayl-lower alkyl, phenyl, phenylmethyl and lower alkylaminocarbonyl, may conveniently be prepared by the introduction of the reactive aster side chain into a starting material of the formula (Wt)» (XXX) following procedures similar to those described for the preparation of the intermediates (XXVI) starting from (XXIII).
Intermediates of the formula (Il~c) -244 4942 may be prepared starting from the corresponding (ΙΙ-a) by hydroxymethylation of the latter in the usual manner with formaldehyde.
Intermediates of the formula (Il-d) M s' a~ (II-d) except those wherein M stands for a mercapto or lower alkylthio group, are conveniently obtained by the introduction of the reactive ester* side chain into a starting material of the formula (XXXI) M (XXXI) The introduction of the C H -w group may be performed following procedures similar to those described for the introduction of the group into starting materials of formula (XXIII). -25Intermediates of formula (II-e) (ii-e) 1 wherein 2·, Ε , Μ', n and W are as 'previously defined,, may be prepared- by subjecting an appropriate alcohol of formula (XXI) to ring closure with an appropriate eyeliziag agent, as described hereinbefore, followed by the conversion of the hydroagrl group of the .thus obtained . intermediate of formula (Sail) into a reactive ester group. • · if (m) cyclization^ reactive ester formation The intermediates of the formula (2X°£) (H-f). -26* 4 S 4 g are conveniently obtained by S-alkylation of an appropriate intermediate of formula (XXXII)wherein M1 is a mercapto group (XXXII-a), following standard S-alkyiating procedures, e.g. with an appropriate halolower alkane and subsequent conversion of the hydroxyl function of the thus obtained (XXXIII) into a reactive ester group.
R1 R2 jrYc V-QH n 2n (XXXII-a) (Il-f) reactive ester formation Intermediates of the formula (H-g) :IH-CC-( lower alkyl) (Il-g) are conveniently prepared by N-acylation of the corresponding amino substituted analog, (II-h), ^>-°ηΗ2η-ν R R‘ (II-h) -27following procedures know in the art, e.g., by.the reaction.of (ΧΙ-h) with an appropriate lower alkylcarbonyl halide or with an anhydride derived from an appropriate lower alkylearboxylic acid.
The intermediates of formula (IV) are obtained by the condensation of aa appropriate reactive ester of formula (XXXIV) with a piperazine or piperidine derivative of formula (III) followed by the reduction of the nitro group of the thus obtained intermediate (XXXV) to an amino group according to standard nitro-to-amine reduction procedures , e.g., by the reaction of the nitro compound with nascent hydrogen or by catalytic hydrogenation ia the presence cf aa appropriate catalyst such as, for essaiaple, laasy-aiekel. + (m) ,Ar \.„2 Ar nitro-to-amine -^( IV) reduction (XXXV) -284 4 0 4 2 The reactive esters of formula (XXXIV), used as starting materials herein are easily prepared from an alcohol of formula (XX) by the conversion of the hydroxyl function thereof into a reactive ester group following standard procedures as previously described herein.
The intermediates of formula (v) may be obtained by the condensation of a reactive ester of formula (XXXVI) with a pipera2ine or piperidine derivative of formula (IH) p-s^Voaaan-w (III) . ^(V) ίο (XXXVI) The reactive ester (XXXVI) used as a starting material herein is in turn prepared by introducing the GnH2nv group into a starting material of formula (XXXVII) (XXXVII) following the procedures described, hereinbefore.
‘ She intermediates of formula (XVI) may be prepared by the reaction of a reactive ester of formula (II) with a piperazine derivative of formula (XXXVIII) wherein q is aa appropriate protecting group such as, for example, phenylmethyl er lower alkylosyearbonyl, and subsequently eliminating said, protecting group q from the -so-obtained intermediate (XXXIX) f ollowing standard known procedures, ' for example, by catalytic hydrogenation using palladiua-=pn«=charcoal catalyst when q stands for phenylmethyl, or by alkaline hydrolysis when q stands for lower alkylosyearbonyl.
(II) + O -=_> Β^ηΗ2η"\3Ν"° (XXXVIII) (mix) elimination of q —...............:................> (XVI) -30= may alternatively be prepared, by.the reaction of (XXXVI) with (XXXVIII) to obtain an intermediate of formula (XL) and subsequently eliminating the protecting groups P and 0 by appropriate procedures as generally known in the art.
(XXXVI) + (XXXVIII) (XVI-a) (XL) elimination of -> Q Intermediates of formula (III) wherein A is fand m is 0,. (Hl-a), sre generally known and they may all be prepared by known methods.
Sugh intermediates '(III-a) may for .example, be prepared by first subjecting an appropriate aroyl halide to a Priedel-Crafts reaction with an appropriate arene to ob-. 1 2 tain an Ar , Ar -methanone which in turn is reduced in the usual manner, e.g., with sodium borohydride to the corresponding methanol. The latter is then converted into a reactive ester (XVII) following standard procedures of preparing reactive esters starting from alcohols and the desired intermediates (ΙΙΙ-a) are subsequently obtained by the reaction of (XVII) with piperazine.
The intermediates of formula (III) therein A is and a is 1, (HI-b), may conveniently be prepared by 0alkylation of a 4~i>iperidiaol of formula (ai) wherein Q is an appropriate protecting group as previously defined with aa appropriate reactive ester of formula (XVII), followed by the removal of the protecting group of the so-obtained " (XIII) in the usual manner.
(XM) (XVII) (an) removal of Q ——-----~> (ni-b) The primary starting materials used in all of the foregoing preparations are generally known and they may all be prepared by known methods.
Th® compounds of formula (I) may be converted to the therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid, such as, ' -=~?.an inorganic acid, such as hydrohalic acid, e.g., hydrochloric-or hydrobromic, and sulfuric acid, -32nitric acid or phosphoric acid; or an organic acid, such, as, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2-butensdioic, (S)-2-butenedioic, 25 hydroxybutanedioic, 2,3-dihydroxybutanedioie, 2-hydroxy1,2,3-propanetricarboxylic, benzoic, 3-phenyl~2-propenoie, -hydrcxybenzeneacetic, ^ethanesulfonic, ethanasulfonic, benzenesulfonic, 4-.aethylbenze»esulfonic, cyclohsxanesulfamic, 2-hydroxybenzoic or 4-amino-2-hydroxybenzoic acid. Conversely, the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof possess strong anti-anaphylactic and antihistaminic properties and as such they are useful agents in human and animal therapy. The useful anti-anaphylactic and antihistaminic properties of the compounds of this invention are clearly demonstrated by the results obtained in the test procedures described hereafter.
It is emphasized that the compounds listed in the accompanying tables are not given for the purpose of limiting the invention thereto, but only to exemplify the useful anti-anaphylactic and antihistaminic properties of all the compounds within the scope of formula (I). -33— A. Materials and methods. a) Anti-anaphylactie and antihistaminic effects in vivo11.
The anti-anaphylactic and aatihistasiaic effects of the subject compounds (X) and salts thereof are studied in vivo" in guinea pigs.
Guinea pigs, weighing between 400 and 500 g, are sensitized to ovalbumin by subplantar (s.p.) injection of 0.05 ml of antiserum in the left hind paw. The animals §r© then star'ved and orally treated, 24 hours after the sensitisation, with saline (= control animals) or a particular dose of the compound under investigation.
' The histamine injection (at a dose of 50 jig) was given s.p. in th® right hind paw 2 hours after the 'oral pretreataent with the compound. The diameters of both hind paws are first measured before the histamine injection is given and again minutes thereafter. The animals are challenged intravenously with 0.5 ag of ovalbumin 30 minutes after the histamine injection. All control animals develop'typical primary anaphylactic shock symptoms (coughing, difficult breathing, convulsions) and 85% of. these control animals die whithin 15 minutes after the ovalbumin injection. Protection against death is used as the criterion for possible drug effects and the estimated BD^g-value, i.e. the oral dose whereby the protection is observed in 50% of the guinea pigs, is listed in the tables below.
The median histamine paw eedema in 200 control animals minutes dftei the histamine injection is 15 units (1 unit =a 0.1 ma). Enactions below 10 units, oceuring in less than 5% of the control animals are defined as effective in30 hibition of histamine ea dema in the compound-treated animals and the oral dose-levels Whereby this effective inhibition is seen, is also listed in the following tables. -34= b) Anti-histamine activity in vitro.
Guinea-pig ileum strips are suspended in a 100 ml Tyrode bath at 37.5°C with a preload of 0.75 g and gassed with 95% 02 and 5% 'SOg.
The histamine - (.0.5 mg/liter) induced spasms are recorded Kymographically with an isotonic lever giving a 5fold magnification. The interaction of the compound to be tested (5 minutes incubation time) with the agonist is studied and tha tables below give the effective con10 centration (in mg,7!) of the different compounds whereby a significant inhibition (50%) of the histamine-induced contraction is measured.
» , As a result of the foregoing tests, the subject compounds (I) and pharmaceutically acceptable salts thereof are generally found active as anti-allergic agents in doses ranging from about 0.25 to about 20 mg/kg body weight upon, systemic administration to warm-blooded animals.
In view of their useful antihistaminic and anti20 anaphylactic activity, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, an effective antihistaminic or anti-anaphylactic amount of the particular compound, in base or acid-addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable diluent carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. 355 A These pharmaceutical compositions are desirable in unitary dosage fora suitable, preferably, for administration- orally, rectally or by parenteral injection. For example, in preparing -the .compositions... in .oral, dosage form, any of the usual pharmaceutical media say be employed, such as, for example, water, glycols, oils ana alcohols ..in .the case of' oral liquid preparations such as suspensions, syrups, elixirs and solutions?, or solid carriers such as starches, sugars, kaolin, lubricants, binders and disintegrating agents in the case of powders pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit fora, in which case solid pharmaceutical carriers are obviously employed» For parenteral eomposii^ns, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for· example, to aid solubility, say be included. Injectable solutions, for example may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution» Injectable suspensions say also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Acid addition salts of (I), due to their increased water solubility over the corresponding base fora, are obviously more suitable in the preparation of aqueous compositions. -364® It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired, therapeutic effect ia association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable, solutions ar suspensions, teaspoonsful and tablespoonsful and segregated multiples thereof. -37,4943 ® ο)·\ GJ® rt g % (3-ri S •rt 0) iJ rl ϋ rt Cm >i © w girt (3 10 fe =s s (ΛΐΛ CM CM tf\ OJ CM Ϊ- VO cO CM τ- Ό CO ooo&«o«trdO*o r-T’-CMT-T’OOQ^OQO π f) ^in^coGcoeicovo VOVOtncOCMCOVQvVOOVS^lAtA ο ο σ ο ο ο e* ο o cu· o ·- o © © © 0 © CM OJ Λ g □ s '.r © >rt m ’rl <3 kora w s e-ri u g fM Sm «3 0 V3 CM M3 & r^fJWr’OlWSFP-S'Paifl οοοοοοσοοσοοο»ο ο* β » β' β ο o e β' ο ο* ο o ΟΘΘΘΟΘΟΟΘΘΘΘΟ© Λ θ cu Φ©©Φ(!)©Β©©© © © © cn en tn cn cn tn w tn cn cn cn cn cn (Λ as ¢3 ίΰ <3 X <3 cM (ΰ (ΰ ίΰ £ β & & a τ» A & ►<3 pQ & «1 fc. f S S T s S S S3 E S SSS feu fei S 4- 4· S S S' SSS «oioiMwoieiirtnflnfln cn CM eu CM CM cu CM CM ,CM eu eu CM _cm Λ CM cu s. a S3 w a 53 w a a a K a ,s o O o M © o © © © © © « © o © •B0 %β* *w* *S5S* »^a» *e=/ *W »c=s* >at ’("} f=} a o © © © o 64 s s VO s s a E a a a vo vo e** νέ CO co ' ¢0 rl fe. a H a fM o Q o © o o Γ*» 1 1 1 « s 1Λ a ΙΛ ΙΛ a a s ιλ ΙΛ a a a ir\ a a s a a a a a a. a a a a a a •38 * & !'e Table I—a (cont’d) a a a o rt i-l o •rt ¢)^ 1? ?5 cm si j Eg S φ *rf Γ i fa £ H k «5 0 ώ CQ CM (IS eg CM X o* OJ « cn cn d d cn kG (A roi cn A cn OJ o cn V3 cn kO A or o !" A OJ r* cn 9 « β 0 β 1 e· β © o o F* o O ~ Λ O r- ifl t'l CM νβ « OJ VO e ¢. · c ο © o rt o a rt o CM rt o o ΙΛ o o ΙΛ » va o oj »t- o O O Ϊ— 50 VOi »9 5*, Lfi Π vo CM r· CM w « β « » 0 3 O Q rt Q rt rt co ίο o Ο Ο O o o’ o’ o’ o Cj· CVJ σ o e OJ OJ o ’OJ H ol X 0) a) 0! 0) as 0! r> «’ ai X OJ r- (ft B eft eft 0· ω » σι r/i Cft 01 eft kJ a ig H σι W ffl (TS Kj KJ KJ X» o oi A B o as B a ►»4 Λ B B B B ni Jd- *&7 B X s as as B B B X X a n* a- —i rH o o fo & S as as X as B X a 1 a- ST cn sr 4- cn cn rt**.
CM OJ X X o o as s co fo o ι cn oj X o o X ΪΙ d cncncncncn-cncncncncncncn rt*% rt*> rt*» rt** rt** rt**» rt*k rt** rt*» rt·*» rt*. rt*. 01 OJ OJ CM OJ OJ CM OJ 01 01 Ol iEBBMEBSXBBBS οοόοοοοοοοοο B B X X B 1 I i O o Ol o COO CM B 1 ! I Β O *-*· o o B 0—0 1 CM 1 CJ U5 II AX A 1 1 Oi I OJ X Q X O Ol ϋ X kO X X coo B S3 kO u x x x B EC B rH ϋ in X X X -39449 43 Table I-a (cont’d) -404 4© d s ‘43 « Table I-b -41Πη . rt i «0.3 i§0 I’rt W ί&8 E! 0 •rl > •rl c (fi DU •rt ox " 0 C ,- m c= f= co in to m CO Ol CC 03 r- CJ r- CM Ofr « ΟοΟβΟ Q c·- Q o Q t— Ώ CJ CC in Μ 0 CM g «4 rt ft &0 a «r! fcrt > (0 ft fj S fi 3 < 0 « O fs 0 •rt d) O rrt 0-rt 0 g'-'fxrt •rt 2 *rt s e u\ S h o o5 D D 0 B OT-rtCIM •rt £.¾ g ALigL fl O p a rrt fi oi m o '03 CM a P*.
Ti w sa © rineocnein Ifl ΙΛ « (Μ Ο ι- r οι ο ηι (ί 01 Ο r ο Ο θ r Q r 0 0) id A CC σι co in o σ a in in r· r» CU © Ο O £» ο α © ο ο © o oooooooo in θ M OJ O © © © © © _ 0 irt m m © 00a 4 4 n 0 0 0 OT OT 01 B © © B Ol O a a o O O awsw x *£=· s * se· » s as rt rt , fc O O X Β v ci 0 ,a rs OT if rt .-I a ot © © (rt κ ΰ 0 S § n oi o n OT fc, I ν fc. b, I I v a ca(rt b. © ί r cc fe, 6, a 4 OT OT OT OT OT OT . V V V V Z-A , /X. χχχ. χχ, yra, MOI Ol W 0 ΟΙ ΟΙ M.0 01 asaaaaaaaa O.OOOOOUOOU ? D g 0 F" 04 · rt rt fp. (S co 1 i a £ 1 0 K a • 1 o 0 ΙΛΗ rt a a Λ M? >1 ft ο σ IH a a a a a cc a © a a a s □ I W Table -43· N^N- (CHo), { Η 3 J base 5 0.0025 S O„16 I 0.16 co Table I-e The following 'examples are intended to illustrate but not to limit the scope of the present invention. Unless otherwise stated all parts therein sre by weight. -464© 410 Example I To a stirred and hot mixture of 54 parts of 1,3dihydro-1-(phenyImethyl)-2H-benaimidazol-2-one, 47.25 parts of 1-brcmo-3-chloropropane and 6 parts of Ν,Ν,Νtriethylbenzenemethanaminium chloride are added dropwise 450 parts of sodium hydroxide solution 60% at 60°G. Upon completion, stirring is continued for 6 hours at 60°c. The reaction mixture is cooled and poured onto water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized frcm 2,21-oxybispropane, yielding, after drying, 42 parts (53%) of 1-(3-chloropropyl)-1,3-dihydro-3-(phenylmsthyl)-2H-benzimidazol2-one.
Similarly were prepared: ) -Cl /H / V Al 6 S L R1 n boiling point CH?=C(CH<,) 5-CH3 3 140°C at 0.015 mm. pressure CH?=C(CH^) 6-CH, 3 Ϊ40°0 at 0.02 mm. pressureC6H5 5-C1 3 - CHjjeCiCH,) H 4 - CHp-CiCH^) ti 5 - 3H2-C(CH3) H 6 "47Example II Following the procedure of Example I and using a® equivalent amount of an appropriate 1H-bensimidazole as a starting material there were obtained as a residue M McnH2n ch3 (¾ Θ (ch2)3 c2h5 (CH2)3 H CH2-ipH-CH2 ch3C6H5 (0H2)3 , CK3 *49 Example III A mixture of 20 parts of 3-/j(2-amino-4-chlorophenyl)amino7-1-propanol, 50 parts of acetic acid and 150 parts of hydrochloric acid solution 4N is stirred and refluxed overnight. The reaction mixture is cooled and evaporated. The residue is dissolved in water and the solution is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2' oxybispropane, yielding 6.5 parts (28%) of 5-chloro-2methyl-1H-benzimidazole-1-propanol.
Similarly there was prepared 5-chloro-2-ethyl1H-benzimidazole-1-propanol by the reaction of 3/^2-amino-4-ehlorophenyl)amino7'"l-propanol with propanoic acid.
Example IV To a stirred and refluxing (water-separator) mixture of 30 parts of 3-/T2-amino-4-chlorophenyl)amino/ 1-propanol and 0.1 parts of 4-aethylbenzenesulfonic acid in 405 parts of methylbenzene is added dropwise a solution of 34 parts of cyclohexanecarboxaldehyde in 45 parts of methylbenzene. Upon completion, stirring is continued for 1 hour at reflux temperature and with water-separator. The methylbenzene is removed by evaporation in vacuo and the residue is triturated in 2,2'oxybispropane. The product is filtered off and dried, yielding 16,5 parts (38%) of 5-chloro-2-cyclohexyl-1Hbenzimidazole-1-propanol; mp. 95°C.
Example V A inixture of 30 parts of 3-/j2-amino=4-chloro~ phenyl)amino/-1-propanol, 44.8 parts of sodium c{~hydroxybenzeneethanesul£onate and 120 parts of ethanol is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The ’extract is dried, filtered and evaporated, yielding 45 parts (100%) of 5-chloro=2=(phenylmethyl )=1H-benzimidazole-1-propanol as a residue.
Similarly there was prepared 6~chloro=2~cyclohexyl-1H-benzimidazole-1-propanol; mp. 120.1 °C by the reaction of 3"/r2"amino"5=chlorophenyl)airtino)7=1-propanol vzith sodium ft -hydroxycyclohexanemethanesulf onate.
To a stirred mixture of 93 parts of 3-(2-aminophenyl) amino-1-propanol, 45.5 parts of potassium hydroxide and 600 parts of ethanol 85% in water ar® added dropwise 60.8 parts of carbon disulfide. Upon completion, stirring is continued for 6 hours at reflux temperature. The Reaction mixture is evaporated and the residue is taken up in 1500 parts of water. The Whole is filtered over Hyflo (BegisierafcTKsa&.iJjirk) and the filtrate is acidified with acetic acid. Theoily product solidifies on scratching. It is filtered off, washed vzith water and dried, yielding 92 parts (78.9%) of 2-mercapto1H-benzimidazole-1-propanol; mp. 110°C. .1 A mixture of 20. S parts of a-sfercapto-IE-bensaiaidazole-l-propanol, 15.62 parts of iodomethane and 120 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated and the residue is dissolved in 500 parts of water. The solution is filtered over hyflo and the filtrate is alkalized with solid potassium hydroxide. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 19 parts (85.5%) of 2-(methyithio)-1H-benzimidazo3&"1-propanol lo as a residue, To a stirred mixture of 19 parts of 2-(methylthio)1H-benzimidazole-1-propanol, 15.2 parts of N,K-diethylethanamine and 195 parts of dichloromethane are added dropwise 11.5 parts of methanesulfonyl .chloride. Upon completion, stirring is continued for 1 hour at reflux.
After cooling, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 19 parts of 3-/2-(methylthio)-1H~benzimidasol-1yl/propyl methanesulfonate as an oily residue.
Example VII A mixture of 30 parts of IH-benzimidazole, 49 parts of 2-(4-chlorobutoxy)~tetrahydro-2H-pyran, 21 parts of potassium hydroxide and 200 parts of ethanol is stirred and refluxed overnight. The reaction mixture is cooled, to room temperature, filtered and tha filtrate is evaporated. The residue is stirred in water and acidified with a diluted hydrochloric acid solution. The'whole is stirred and heated for 30 minutes in a water-bath. After cooling to room temperature, the product is extracted with methyl30 benzene. The aqueous phase is separated and alkalized with ammonium hydroxide. The product is extracted with dichloromethane. The extract is dried, filtered and evaporated, yielding 5θ parts of 1H-benzimidazole-1-butanol as an oily residue. -51Example VIII To a stirred mixture or 5 parts of 4-chloro-1,3dihydro-3=.( 3-hydroxypropyl)-2H-benzimidazol-2-one and 75 parts of trichloromethane are added dropwise 8 parts of sulfinyl chloride. Upon completion, stirring is continued for 3 hours at reflux temperature. The reaction mixture is cooled and evaporated. The residue is stirred in a small amount of 4-methyl-2-pentanone. The product . is filtered off and dried, yielding 3.5 parts of 4-chloroio 3"(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one.
In a similar manner the following 1-(chloroalkyl )-1 H-benzimidazoles were prepared: (CH2)a-Cl M n R1 Base or Salt form Melting PointC6H5-CH2 3 5-C1 base - ch3 3 5-C1 base -C2H5 3 5-C1 base - 0 3 5-C1 HCl 211„7OC C6HrCH2 3 H base 112°C -sx- M n Base or melting point Θ 3 6-C1 HCl 227.5°C c2h- 2 H base H 4 . H base .
Example IX k mixture of 113.2 parts of 1,2,4-trichioro-5nitrobensene, 75 parts of 3-amino-l-propanol, 0.2 parts of potassium iodide and 200 parts of butanol is stirred and refluxed overnight. The butanol is removed by evaporation in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times -with water, dried, filtered and evaporated. The oily residue is purified by columnlo chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated.
The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propenol, yielding 31.7 parts of 3-/(4,5-dichloro-2-nitrophenyl)amin^-1-propanol; mp. 97 °C.
-S3Similarly were prepared: . 3-|/2-nitro=4-(trifluoromethyl)phenyl7aminoj-1-propanolj and mp. 74.9®C. ethanol; Example X To a stirred mixture of 39.2 parts of 3-(2-nitrophenyl)amino-1-propanol and 225 parts of trichloromethane are added dropwise 35.7 parts of sulfinyl chloride (exothermic reaction: temperature rises to 45®C)„ Upon completion, stirring is continued for 6 ' hours at reflux temperature. The reaction mixture is evaporated, yielding 43 parts (100%) of N-(3-chloropropyl)-2-nitrobenzenamine as a residue.
Similarly were prepared: N-(3-chloropropyl)-2-nitro=4—(trifluoromethylJbenzenamine as a residue; 4,5-dichloro-N-(3-chloropropyl) -2-nitr obenzenamine; ’ sap. 78®C? and N-(2=chloroethyX)-2-nitro-4-(tri£luoromethyl)benzenamine, Example XI A mixture of 21.5 parts of N-(3-chloropropyl)2-nitrobenzenamine, 22.68 parts of 1-(diphenylmethyl)piperazine, 20 parts of Η,Ν-diethylethanamine and 180 parts of Ν,Ν-dimethylacetamide is stirred and heated for 6 hours at 100°C. The reaction mixture is evaporated and the residue is taker, up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated, The residue 10 is crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropans. The product is filtered off and dried, yielding 15.5 parts (36.9%) of ^-(diphenylmethyl )-N-(2-nitrophenyl)-1-piperazinepropanamiae hydrochloride; mp. 228°C.
Similarly were prepared: H-(4ι5-dichloro-2-nitrophenyl)-4-(diphenylmethyl)-1piperazinepropanaaine as a residue; 4-(diphenylmethyl)-N-/2-nitro-4-(trifluoromethyl)phenyl7-1-piperazinepropanamine? mp. 113.7°C; snd 4-(diphenylmethyl)-N-/2-nitro-4-(tr ifluoromethyl)phenyl7-l-piperazineethanamine? mp. 152.1 °C.
Example XII A mixture of 15 parts of 4-(diphenylmethyl)-K(2-nitrophenyl)-1-piperazinepropanamine hydrochloride. in 160 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Eaney-55nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over:Hyflo and the filtrateis evaporated. The solid residue is crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding 12 parts (78.9%) of N-(2-aminophenyl)-4-(diphenylmethyl)-= 1-piperazinepropanamine hydrochloride; mp. 223.1®C.
Similarly were prepared! 4,5-dichloro-N1 -]3-/4- (diphenylmethyl )-1 -piperaziny^propyl1-1,2-benzenediamine as an oily residue N1 - ^3=^4-(diphenylmethyl)-1-piperazinyl/propyl)-4(trifluoromethyl )-1,2-benzenediamine; and N1 -|2-/4-(diphenylmethyl) -1 -piper azinyjTethyl /-4-( trifluoromethyl)-! , 2-benzenediamine as an oily residue.
Example Kill A mixture of 60.5 parts of 1-(3-chloropropyl)1,3-dihydro-3-(l -methylethenyl )-2H-benzimidazol-2-one, 31.68 parts of 1-(phenylmethyl)piperazine, 21.2 parts of sodium carbonate, 0.1 parts of potassium iodide and 400 pants of 4-methyl-2-pentanone is stirred and refluxed.
-SVfor -20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and evaporated, yielding 70 parts (100%) of 1,3-dihydro-l-(l-methylethenyl )-3-|3-/J-(phenyImethyl)-1-piperaziny±7propylJ2H-benzimidazol-2-one as a residue.
Similarly was prepared 1,3-dihydro-l- £2-/3-(phenjamethyl)-1-piperazinyl7ethyl I -2H-benzimidazol-2-o»ej mp. 136.5°C.
Example xiv To a stirred solution of 70 parts of 1,3-dihydro-l(•j-methylethenyl)-3- £ 3-/3-(phenylmethyl)-i -piperazinyl/propyij-2H-bffittsimidaz0l-2-cne in 240 parts of ethanol are added 55 parts of hydrochloric acid solution 6N.
The whole is stirred for 2 hours at 4O.-5O°C. The reaction mixture is evaporated end the residue is taken up in a diluted ammonium hydroxide solution. The oily product is extracted with trishloromethane. The extract is dried, filtered and evaporated, yielding 63 parts (100%) of 1,3-dihydro-i-^3-/4-(phenylaethyl)-1-piperazinyl/propylj2H-benzimidazol-2-one as a residue. ~51~ Example XV A mixture of 63 parts of 1 ·, 3-dihydro-l -|3- Similarly was prepared: 1,3-dihydro-l-/2-(1-piperazinyl)ethyl/-2H-benzimidazol2-one; mp. 122.6°C.
To a stirred mixture of 20 parts of aluminium chloride and 100 parts of fluorobenzene ar® added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. Upon completion, the fixture is heated to reflux and stirred at reflux temperature for 5 minutes. The reaction mixture is poured onto crushed ice and the product is extracted with 1,1‘-oxybisethane. The extract is dried and evaporated, yielding 30 parts of (2,4-dichlorophenyl)(4-£luor0phenyl)methanone as ah oily residue. -£8· • Similarly was prepared: (4-fluorophenyl) (4-pyridinyl)methanone; mp. 85.5°C.
Example XVII To a stirred and refluxing mix-cure of 23.4 parts of (4-chlorophenyl)(2-fluorophenyl)methanone in 280 parts of 2-propanol are added portionwise 3.7 parts of sodium borohydride. Upon completion, stirring is continued for 2 hours at reflux temperature (+ 80°C). The reaction mixture is cooled and decomposed by the addition of water. The 2-propanol is evaporated and the residual product is extracted with trichloromethane. The extract is dried, filtered and evaporated, yielding 23.6 parts of 4-chlOro-^-(2fluorophenyl)benzenemethanol as a residue.
Similarly were prepared: 2,4-dichloro-^-(4-fluorophenyl)benEenemethanol as a residue; 4-^fluorophenyl)-4-pyridinemethaiiol? mp. 138»2°C. «(-(4-fluorophenyl)-3«-pyridinemethanol hydrochloride; mp. 15θ.3°ΰ; and 4-methoxy-oj- S'}Example XVIII A mixture of 22 parts of 2,4-dichloro-^-(4-fluorophenyl)benzenemethanol and 240 parts of hydrochloric acid solution 12N is stirred for 40 hours at room tempera5 ture.' The reaction mixture is poured onto ice-water and the'product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 13.2 parts of 2,4-dichlor©-l-/"a-chloro-a-(4-Eluorephen.yl)it!sthylfjbenzene; lo bp. l46eC at 0.15 mm. pressure.
Similarly were prepared; 1-^C-chloro-i{-(4-methoxyphenyl)methyl7-3-(trifluoro-' · 'methyl)benzene as a residue; and · '1 "ZS-chlorcra- (4-ms£^lpNenyl)msth^Z -A-fluocctoenzeiS as a residue.
Example xxx To a stirred· mixture of 23.6 parts of «^-chloro-^(2-fluorophenyl)benzenemethanol in 108 parts of benzene are added dropwise 24 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued first for 5 hours at reflux temperature and further overnight-at room temperature. The benzene is evaporated and the residue is distilled, yielding 2o 16.5 parts of l-ehloro-4-/0?-chloro-oi-(2»£luorophenyl)methyl/benzene; bp. 122-125 °C at 0.1 mm. pressure. -feO*4-9 *3 Similarly were prepared: 3-/f-chloro-t/- (4-fluorophenyl )methyl7?yridine hydrochloride as an oily residue; 3-/7-chloro-ci-(4-chlorophenyl)methyl/pynidine hydrochloride as a residue; 4-/^-chloro-oi-(4-fluorophenyl Jmethyl/pyriQine hydrochloride; mp. 193-2OOSC; 1-(a-chloro-a-methylpriKhyi) -2,3-diraethylbenzene; bp. 137°C at 0.7 mm. pressure; 1- (o-chloxo-a-metfcyIpheny1)—2,4-dimethylbenzene; bp. 137eC at 0-7 mm. pressure; 2- (α-qhloro-a-methyIpheny1)-1,4-dimethylbenzene; bp. 136°C at 0,7 mm. pressure; l-(a-chloro-a-methylphenyl)-2-rIuorobenzene; bp. 10810S°C at 0.4 mm. pressure; Example XX A mixture of 121 parts of piperazine, 54 parts of -chloro-oj-(4-chlorophenyl)methyl/pyridine hydrochloride and 315 parts of N,N-dimethylformamide is stirred for 20 hours at room temperature. The reaction mixture is evaporated and 250 parts of water are added to the residue. The product is extracted- with methyl’s' benzene. The organic phase is washed vzith water and extracted with an acetic acid solution 10%. The acid aqueous phase is alkalized vzith a sodium1hydroxide solution 60% and the product is extracted again vzith methylbenzene. The extract is dried, filtered and evaporated. The oily residue is converted into the nitrate salt in ethanol. The salt is filtered off, washed vzith ethanol and vzith 2,2*-oxybispropane and crystallised from ethanol, yielding 48 parts of 1 -/[-(4-chlorophenyl)-<=( 10 (3-pyridinyl)methyl7piperazine trinitrate; mp. 132.9°C.
Similarly were, prepared;' -^-(4-chlorophenyl)- 1-/? -(4-fluorophenyl)-ej-(4-pyridinyi)methyl7piperazine ? mp. 108.4®C; * 1-/( 2-chlorophenyl)(3-chlorophenyl)methyl7piperasine; 1-/(2-fluorophenyl)phenylmethyl7piperazine ethanedioats (m); mp. 195.5θΟ; -/(4-f luorophenyl) (4-methoxyphenyl Jsiethyl/piperazine ethanedioate (-1:2); mp. 280.1 °C; and -/(4-nitrophenyl )phenylmethy^piperazine dihydrochloride.
Example XXI A mixture of 21.5 parts of ethyl 4-hydroxy1-piperidinecarboxylate, 35.2 parts of bis(4-fluorophenyl) bromomethane and 8.6 parts of potassium carbonate is stirred and heated in an oil-bath at 14O°C for'3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, a diluted hydrochloric acid solution and a sodium bicarbonate solution, dried, filtered and evaporated. The forerun is distilled off (bp. till 143°C at 0.5-1 mm. pressure), yielding 29 parts of ethyl 4- Similarly was prepared: ethyl 4-(diphenylmethoxy)-l-piperidinecarboxylate; bp. 15C°C at 0.4 mm. pressure.
Example XXII A mixture of 29 parts of ethyl 4-/his (4-fluorophenyl )methoxy7~l-piperidinecarboxylate, 25 parts of potassium hydroxide, 1 part of water and 160 parts of 2-propanol is stirred and refluxed for 4 hours. The solvent is evaporated and water is added to the residue. The product is extracted with methylbenzene. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is converted into the hydrochloride salt in 4-methyl-2-pentanone and 2-propanol at room temperature. The salt is filtered off and dried, yielding 20.5 parts (78%) of 4-/bis(4-fluorophenyl)methoxy^Piperidine hydrochloride; mp. 161.8°C. -uSimilarly was prepared; 4—(diphenylmethoxy)piperidine hydrochloride; mp. 209o8°Co Example mn A mixture of 5 = 3 parts of 1-(3-chloropropyl)-i ,3dihydro-2H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4"fiiethyl-2"pentanone is stirred and refluxed overnight with water-separator. After cooling, water is added and the layers are separated. The 4-methyl-2pentanone-phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The. oily residue is crystallized from a mixture of 2„2'-oxybispropane and a small amount of 2-propanol. The product is filtered off and dried, yielding 2 parts (23%) of 1 -^3-/(4-(diphenylmethyl)-11,3-dihydrO"2H-beasimidaaol-2-one: mp. 15S.S°C.
In a similar manner the following . compounds were prepared in free base fora or in the fOra of en aeid addition salt after treatment of the free base v/ith an appropriate acids * d 8 4 2 IS / / 44® 43 Example XXIV In an analogous manner as described in Example XXIII there were prepared: 1-23-{4-/bis(4-fluorophenyl)methyl7-l-piperazinylJpropy^7-1,3-dihydro-2H-benzimidazol-2~one; mp. 197=3°C by the reaction of i,3-dihydro=1-(3-hydroxypropyl)=2H-benzimidazol-2-one methanesulfonate with 1-/Bis(4-fluorophenyl)methyl7piperazine; 1- ^3-/4-(diphenylmethyl )-1-piperazinyl7propylj-1,3dihydro-3-methyl-2H-benzimidazol=2-one dihydrochloride hydrate; mp. 201»8°C by the reaction of 1,3-dihydro-l-(3-iodopropyl)-3-methyl-2H-bensisaidazol-2-one with 1-(diphenylmethyl)piperazine; > · 3-^3-/4-(diphenylmethyl)-1-piperazinyl7gropylj2(3H)-bensothiazolone dihydrochloride, hemihydrate; mpo. 186.1 °C by the reaction of 3-(3-bromepropyl)2(3H)-benzpthiazolone with 1-(diphenylmethyl)piperazine; and 3-^3-/4-(diphenylmethyl)-1-piperazinyl/propylI2(3H)-benzoxazolone dihydrochloride; mp. 212.4°C by the reaction of 3-(3-chloropropyl)-2(3H)-bensoxazolone with 1-{diphenylmethyl)piperasin@.
Example XXV A mixture of 6.95 parts .of 1-(5-shloropentyl)25 1„3-dihydro-3-(l-methylethenyl)-2H-benzimidazol-2one, 5.15 parts of 1-(diphenylmethyl)piperaz2.ne, .30 parts of sodium carbonate, 0.1 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone is -is10 stirred and refluxed overnight with water-separator. The reaction mixture is cooled to room temperature, water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is stirred and refluxed for 30 minutes with 12 parts of a hydrochloric acid solution in 40 parts of ethanol. The whole is evaporated and the residue is crystallized from ethanol, yielding 5 parts (46%) of 1- ^5-/4-(diphenylmethyl)-l-piperazinyl7pgntylj"l,3dihydro-2H-bensimidazol-2-one dihydrochlorids hydrate; mp. 215„3°C.
Similarly were prepared: . « Λ Z-x • ;N-(CH2) -N b'-CH (/ i Ar Γ7 Ar"1 Ar2 Base or Salt form melting point in°C i 5 4-F-C6H4 4-F-C6H4 2UC1.H2O 203.7 I 4C6H6 4-F-C6H4 base 172.3 3C6H5 2-Cl-C6H4 03.SG 149 3 3-Cl-C6H4 2-Cl-CgH4 hcXSG· KqO 139.1 3 c6h5 2,4-Cl2- base 160.1 c6h3 6C6H5C6H5 base 139.7 6 4-F-C6H4 4-F-C6H4 2HC1 204.5 j i ..... Ϊ -tv Example XXVI To a stirred solution of 76 parts of 1-ρ-=Α(diphenylmethyl )=1 -piperazinyl/propylj -1,3-dihydro3-(lymethylethenyl)-2H-benzimidazol-2-one in 280 parts of .ethanol are added 120 parts of hydrochloric acid solution and 250 parts of water. The whole is stirred for 30 minutes at room temperature. Upon cooling in an ice-bath, the product is precipitated. It is filtered off, washed with 2-propanone and with 2,2’-oxybispropane, and dried, yielding 43 parts (55%) of 1{3-/4- (diphenylmethyl) -1 -piper azinyl/propyl j-1,3-dihydrO"2H-bensimidazol-2-one dihydrochloride hydrate; mp. 237.5°C0 Similarly were prepared; if HK M-C H„ R1CnH2n Ar1 Ar2 mp. in ®c H (ch2)3 · 3-pyridinyl 4-C1-C5Ha 1€0o & H (ch2)3 4-pyridinyl 4-P-C6H4 183.2 H (ch2)3 4-Cl-CgH4 4-0CH3=CfiH4 199.3 H (ch2)3 c6h5 2-F-C6H4 157.7 5-CH3 (ch2)3C6H5 c6h5 . 178.3 6-CH, (ch2)3 .C6H5CSH5 195.7 H ΟΗ,-ΟΗίσ'Η,)- 4-P-CgH4 4-F-C6H4 17SCH2 - ’ — ------ Example XXVII A mixture of 3.6 parts of If-^2-/4-(diphenylmethyl )-1-piperazinyl/ethylj -4-(trifluoromethyl)1fi -benzenediamine and 1.8 parts of urea is stirred for 3 hours in an oil-bath at 1S0°C. The reaction mixture is cooled, water and trichloromethane are added and tha layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (25:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.5 parts (41.5%) of l-l2~/4"(diphenylmethyl)-l-piperazinyl7*· ethyll-1., 3-dihydro-5-(tri£ luoromethyl )-2H-benzimidazol-2-one; mp. 163.7 °C.
Similarly were prepared: 1- (diphenylmethyl)-1 -piperazinyl/propylj, 3dihydro-5- (trifluoromethyl) -2H-bensimidazol-2-oae; mp. 152.7°C} and ,6-dichIoro-1 - ^3-/4- (diphenylmethyl )-1 -piperazinyl/propyll-1,3-dihydro-2H-benzimidazol-2-one; mp. 214.7°C.
Example XXVIII A mixture of 2.3 parts of 1-^3-/^-(diphenylmethyl)l-piperazinyi/propylJ-1,3-dihydro-2H-benzimidazol-2-one, 4,5 parts of formaldehyde solution 40% and 45 parts of Ν,Ν-dimethylformamide is stirred and heated for 2 hours at 100°C. The reaction mixture is cooled and diluted with water. The precipitated product is filtered off and crystallized from methylbenzene., yielding, after drying, 1.5 parts (66%) of 1 =43-/4-(diphenylmethyl)-1-piperazinyl/ propylj -1,3-dihydro-3- (hydroxymethyl )-2H-benzimidazol-2one; mp. 102.5CC, Example XXIX A mixture of 1.55 parts of acetic acid anhydride, parts of 1=^3-^-(diphenylmethyl)-1-piperazinyl7propylj=· 1,3-dihydro-2H-bsnsimidazol-2-one and 22.5 parts of lo methylbenzene is stirred and refluxed overnight. Water is added to the reaction mixture and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95;5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1.1 parts (33,5%) of i-acetyl-3-^3-/4-(diphenylmethyl)-1piperazinyl/propyl9=1,3-dihydro-2H-benzimidasol-2-one5 mp, 124.4°C. J20 Example XXX A mixture of 1.1 parts of ethyl 2=propenoatep 3 parts of 1 -^3-/^(diphenylmethyl )-1 =piperazinyl7prepyij= 1P3-=dihydro=2H=benzimidazol=2~one, a few drops of δϊ,ϊί,ΐίtrimathylbenzenemethanaminiw hydroxide solution 40% in methanol and 25 parts of 1,4-dioxane is stirred end refluxed for 24 hours, The reaction mixture is evaporated. i 4 9 4 2 The residue is purified by column-chromatography over silica gel using a mixture of trichloro- . methane and methanol (95:5 ) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanol and ethanol. The salt is filtered off and dried, yielding 1.4 parts (32.5%) of ethyl 3-^3-/4-(diphenylmethyl )-^piperazinyl/propyl ( -2,3-cihydro-2-oxo-lH-benzimidazole-l-propanoate dihydrochloride. dihydrate;; mp. 204°C.
Example XXXI A mixture of 3 parts of 1- (diphenylmethyl ) -1 -piperazinyl7propyl£-1,3-dihydro-2H-benzz imidazol-2-one, 1 part of isocyanatomethane and 25 parts of 1,4-dioxane is stirred and refluxed overnight, The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture cf trichloromethane and methanol (95:5) as 'eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2’-oxybispropane, yielding 0.3 parts (23.5%) of 3-[3-^-(diphenylmethyl)-1-piperazinyl/propylj-2,3-dihydro-U-methyl-2-oxo-lH-benzimidazole1-carboxamide; mp. 153.1 °C.
-ISExample XXXII To a stirred mixture of 9.4 parts of 1-^3-^4-(diphenylmethyl)-1-piperazinyl7propyl>-1,3-dihydro2H-benzimidazol-2-one and 180 parts of methylbenzene are added 0.8 parts of sodium hydride dispersion 75% and the whole is stirred and heated for 60 minutes at 90°C. After cooling to 30°C, 0.2 parts of 2,3,11,12-=dibenzo1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene are added and stirring is continued for 10 minutes. Then there are added 4.2 parts of ethyl 2-bromoacetate and the mixture is stirred and refluxed overnight.
The reaction mixture is cooled to 90’C, 50 parts of water are added and the layers are separated while hot. The organic phase is evaporated,'yielding 10 parts of ethyl 3- diphenylmethyl )-1 -piperaziny^propylj-2,3-dihydro-2-oxo-l H~benzimidazo3s-1-acetate as a residue.
A mixture of 9.8 parts of ethyl 3-^3-/4-(diphenylmethyl)-1-piperazinylZpropylj-2,3-dihydro-2-oxe-1Hbenzimidazole-1-acetate, l.2Jparts of sodium hydroxide and 150 parts of water is stirred and refluxed for 5 minutes {* 80°C). The reaction mixture is filtered and the filtrate is acidified with acetic acid to pH 5.86; a· sticky precipitate is formed. It is separated and crystallized from ethanol and water. The product is filtered off and dried in vacuo at l00°c for 3 hours, yielding 6 parts of 3- ^3-23"(diphenylmethyl )-1-piperaziny^propyl j -2,3-dihydro-2-oxo-1 H-benzimidazole-1 acetic acid hemihydrate; mp. 138.7°C.
Example XXXIII A mixture of 5.2 parts Qf ijS-dihydro-l-./S-ClpiperazinyX)propyX7-2H-benzimidasol~2-ene, 5.28 parts of 2--(-a-chloro-a-methylpheny1)pyridine hydrochloride, 5.3 parts of sodium carbonate and 90 parts of N,H-dimethylformamide is stirred and heated overnight at 50°C. The reaction mixture is cooled and poured onto ice-water.
The product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentsnone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 2 parts (23,4%) of 1,3-dihydro-l/3-^4-/phenyl(2-pyridinyl)raethyl7-1-piperazinyljpropyl/2H-benzintidazol-2-one; mp. 141.7 °C.
Similarly were prepared: mf^NAr’ /—\ n' (CH„),-N N~CH a J \_y Ar' AT* mp. in °C 3 Pyridinyl 4-F_C,-»a 154.1 3 PyridinylC6H5 162.6 4-f.'-C6H4 4-CH3-C6E4 147. S 4-Cl-CgH4 4-01-C6H4 203.5 4-F-06Ha 2,4-Cl2-CgH3 160.1C6H5 - 2;3-(CI^)?- 163.8C6H3 3-CF--C-H. 4-OCH,-C<-Ha 153.4C6H5 4-CH3-CsH4 178,3C6H5 2,4"(CH^)p" 115.8 • C-H, o 3 c6h5 2,5-(CH3)2- 156.3 . C6H3 iyExample XXXIV A mixture of 4.9 parts of 1-(3-chloropropyl)» IH-benzimidazols, 5.76 parts of 1-/bis(4-£luorophenyl)methyl7pipenazine, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 20 hours with water-separator. The reaction mixture is cooled, water is added and the layers are separated. The organic phase is dried, filtered and -evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2’-oxybispropane. The product is filtered off and dried, yielding 5.5 parts (59.3%) of 1-^/3-|4-/bis (4f luorophenyl )methyl/-1 -piperazinyl jpropyl/’-l H-benz15 imidazole hydrate; mp. 108.4°C.
SisilOly were prepared: ί -Th I B.F O>£ •g-H fc s \ M rt β » ^.kD > O S" CO *C0 -r- r- Cl sf co Cl CJ W S If) ίΛ 0 0 0 0 0 r- kO eo co co CJ w O cf ¢0 τ- Cl v· Cl CJ Cl w s fc fc op „ "< φ 0) CO o Cl e> cn fil za © S’.
A W O o o o CJ Cl CJ Cl CVI c CJ \ 0 ss GJ SJ a JS cn v· «*· tn tn ¢3 H H f3 H (0 H rt «Ή *Q ϋ 0 tQ ϋ o o ϋ as W w a S3 CO CO CO CO CO CO & «5 v v a a '0 VS ο ·ο sP et, ii te"1 J>4 4 «· V fc. a^a^a^a^sfa^ aT a9 y I VO «3 ί VS I O U V o w . s'1 ί · ' .
I.P J, -V'V'vaaaa η η v « « n t . ^-s 0—0 0=0 <—» f"*'· —» <—» ·—' t iiw> >' isWig I co n ns a a a a a w w w ο ο ο ο ο o J d 0 g -Ί5ExamplexXXV Following the procedure of ExampleXXXIV there is prepared 1-^3-/4-(diphenylmethyl )-1 -piperazinyl7propyl^-2-(methylthio)-1H-benzimidazole trihydrochloride. hydrate; mp.-203.4°C by the reaction of 3-^2-(methylthio) -1 H-benzimidazol-1 ~yl7?ropyl methanesulfonate with 1-(diphenylmethyl)piperasine.
Example XXXVI A mixture of 4.37 parts of N-(2~aminophenyl)-4~ (diphenylmethyl )-1 -piperazinepropanamine hydrochloride, parts of carbon disulfide, 2 parts of sodium carbonate and 40 parts of ethanol is stirred and refluxed for 20 hours. The reaction mixture is evaporated and water is added to the residue. The precipitated -product' is filtered off, -washed with water and dissolved in trichloromethane. The solution is dried, filtered sad evaporated. The residue is crystallized from 4=3iethyl2-pentanone, yielding 2 parts (45»5%) of ^^-^-(diphenylmethyl )-1-piperazinyl/propylj-1,3-dihydro-2H-bensimidasole-2-thione; mp. 181,8°C» Example xXXVIl A mixture of 60 parts of M-(2-aminophenyl)-4-=(diphenylmethyl.)-1-piperazinepropanamine, 20 parts of methyl (iminomethoxymethyl)carbamate, 42 parts of acetic acid - and 450 parts of trichloromethaae is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is stirred in water. The latter is '· ·- · - . ’decanted and the residue is taken up again in water.
The whole is alkalized with a diluted ammonium hydroxide solution and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated.
The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 13.5 parts of methyl β- (diphenylmethyl)-1-piperazinyl7propylj-1Hbenzimidazol-2-yl7carbamate; mp. 137.8°C.
A mixture of 12 parts of^methyl y4-^3-/4-(diphenylmethyl)-1-pipera2inyl/propylj-1H-benzimidazol-2-yl/15 carbamate, 60 parts of a concentrated hydrochloric acid solution and 30 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and water is added to the residue. The free base is liberated in the conventional manner with ammonium hydroxide snd extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallised from ethanol. The product is filtered off and dried, yielding 4.3 parts (40%) of 1-^3-/4-(diphenylmethyl)1 -piperazinyl7propyl)-1H-benzimidazol-2-amine; mp. 228.7°C. J .A mixture of 10.7 parts of l-.U"/4"(dipheaylmethyl)-lpiperazinyl7propylj-1H-benzimidazdl-2-amine, 5.1 parts of acetic acid anhydride and 90 parts of methylbenzene is stirred and refluxed for 5 hours. The reaction mixture is evaporated and the residue is stirred in 'water. The whole is alkalized with ammonium hydroxide and the product is extracted with trichlorome'chane. The extract is dried, filtered and evaporated. The residue is crystallized from ethanol. «rlThe product is filtered off and dried, yielding 6.6 parts (56.5%) of N-/T-{3-/3-(diphenylmethyl)-1piperazinyl/propyl (-1,3-dihydro-2H-benzimidazol-2-ylidene. acetamide; mp. l43.36C.
A mixture of 13 parts of 1,3-dihydro-l-/3-(1piperazinyl)propyl/-2H-benzimidazol-2-one, 12.4 parts of 1,1 '~(bromomethylene)bis/benzene7, 6.6 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanona is stirred and refluxed overnight with water-separator. After cooling to room temperature, water is added and the layers are separated. The organic layer is dried, filtered and evaporated. The residue is crystallized from a mixture of 2,2’-oxybispropane and a small amount of 2-propanol, yielding 1-^3-/5=(diphenylmethyl)-1-piperazinyl/propylt-1,3-dihydro2H-benzimidazol-2-one; mp. 153®CO ' Example XXXIX Following tiie procedure of Example)® XVIII and using equivalent amounts of the appropriate starting materials, the following compounds are prepared; -^2-4 4=Zbis (4-£luerophenyl )methyl7-1 -piperazinyl ethyl^-1,3-dihydro-2H-benzimidasol-2-one hemihydrate; mp. 131.5°C; 1-|2-/ΐ-(diphenylmethyl )-1 -piperazinyl/ethylj -1,3dihydro-2H-benzimidazol=2-one; mp. 218®C; and 198°C.
Example XI.4 A mixture o£ 4.8 parts of l-(3-chloropropyl)1,3-dihydro-2H-benzimidazol-2-one, 6.1 parts of 4(diphenylmethoxy)piperidine hydrochloride, 7· 5 parts of sodium carbonate and 200 parts of 4-methyl-2pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water- is added. The layers are separated and the 4-methyl-2-pentanone-phase is dried, filtered and evaporated. The oily residue is purified by column15 chromatography over silica gel using a mixture of trichioromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallised from 4-methyl- Similarly were prepared: -33449 42 B-(CH2)n-0-°-CH Ar* ''Ar2
Claims (20)
1. A compound having the general formula: 3-C Η, -N n 2n A-(0) -CH-Ar Γ.1 , (I) Ar wherein ; 1 9 Ar and Ar are each independently a pyridinyl, phenyl or substituted phenyl group, the substituted phenyl group having I or 2 substituents which are each independently a halogen atom, a lower alkyl, lower alkyloxy, trifluoromethyi or nitro group; m is C or 1; A is a /H- or /, CH- group, provided that when A is / Nthen m is 0 and when A is CH- then m is 1; n is an integer of from 2 to 5 inclusive, provided that when C H. represents a branched alkylene chain, n 2n then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidino or piperazine nitrogen atom; and is ί a) a group having the formula: -855 (herein: 1 2 R and R are each independently a hydrogen or halogen atom, or a lower alkyl or trifluoromethyl group; and Y is an oxygen or sulfur atom, or a possibly substituted nitrogen of the.formula'^N-L wherein L is a hydrogen atom, or a lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyllower alkyl, carboxy-lower alkyl, phenyl, phenylmethyl, lower alkylamino-carbonyl, hydroxymethyl or lower alkenyl group; or b) a group having the formula; G S. x tr N15 wherein: Z '2 12 R R R and R are as above defined; and M is a hydrogen atom, or a lower alkyl, phenyl, phenylmethyl, mercapto, lower alkylthio, amino·, lower alkylcarbonylamino, lower alkyloxyoarbonylamino or cycloalkyl group having from 3 to 6 carbon atoms.
2. A compound having the general formula: r\ B-Cffl- -*N A-(0) -CH-Ar 1 · n 2n V_? ί 2 Ar (I) 1 2 wherein: Ar and Ar are each independently a phenyl or 20 halophenyl group; m is 0 or 1 A is an or 86. /CH- group provided that when Λ is then ro is 0 and when Λ is^>CH- then m is 1; n is an integer of from 2 to 6 inclusive, provided that when C i!„ n 2n represents a branched alkylene chain, then at least 2 carbon atoms are present in the linear portion of the chain linking B with the piperidine or piperazine nitrogen atom; and jj* C a) a group having the formula: / χ γ N- wherein R J and R 2 art each independently a hydrogen or halogen atom, or a lower alkyl’ or trifluoromethyl group; and Y is an oxygen or sulfur atom or a possinly substituted nitrogen of the formula ’’bN-L·, wherein L is a hydrogen atom, or a lower alkyl, lower alkyl carbonyl, lower' alkoxycarbonyl-lowsr alkyl, . phenyl, phenyImethyl, lower alkylaminoearbonyl, hydroxymethyl or lower alkenyl group; or b) a group having the formula S, X N// 12 ' wherein F; and R 4 are as above defined; and 8 M is a hydrogen atom, or a lower alkyi, phenyl, phenyImethyl, mercapto, lower alkylthio, amino, 87, lower alkylcarbcnylamino lower allgyloxycaibonylamino, or cycloalkyl group having frcsn 3 to 6 carbon atcms.
3. 1-{β-¢-(Diphenylmethyl)-1-piperazinyl/pEcpyl}1,3-dihydro-2H-benzimidazol-2-one.
4. 5 4. l-/.3-jj4-/Bis(4-fluorophenyl)methyl7-lpiperazinyljpropyl7-l,3 i dihydro-2H-benzimidazol-2-one. 5- 1-/ 4-^4-/ Bis(4-fluorophenyl)methyl7“l“ piperazinyl^butyl/ - !»3-dihydro-2H-benzimidazol-2-one.
5. 6. 1“{ 4 / 4-(Diphenylmethyl)-l-piperazinyl/butylj1,3-dihydro-2H-benzimidazol-2-one.
6. 7. 1-^3-:/ 4-y(DiphenyImethyl)-1-piperazinyl/pfopy1^ · lfi-benzimidazole. — C — —
7. 8· 1-/ 4-^4-/ (4-Pluorophenyl)phenylmethyV-1piperaz zinyl? butyl7-lH-benzimidazole.
8. 9. 1-/ 4-^4.-/ Bis (4-fluorophenyl)methyl7-lpiperaziny^ butyl7“lH-benziruidazole.
9. 10. A pharmaceutically acceptable acid addition salt of a compound as claimed in any one of the preceding claims. 20
10. 11· A process for preparing a compound having the general formula: 88 E-C IL· -N a 2n A- (0) -CH-Ar J , *n . (Ii Ar or a pharmaceutically acceptable acid addition salt thereof; wherein: 1 2 Ar , Ar, m, A, η, B are as defined in claim 1, which process comprises a) reacting an appropriate reactive 5 ester of the formula: B'-C IL· -W n 2n wherein B' is the same as B defined above but is other than a 2-amino-IH-bonziniidazol-l-yl group of the formula: 1 2 wherein R and R are as defined in claim 1 and W is an appropriate reactive e£ter function derived from the 10 corresponding alcohol, with a compound of the formula: A-{0) -CH m Ar (III) \ . 2 Ar 1 ') wherein Ar ', Ar' and m are as above defined in order to prepare a compound of the formula: B ’- C n i! 2n‘ M ΛΛ A-{O) m ~CH Ar (I*) \ 2 Ar or b) decarboxylating a compound of the formula: NH-COO(lower alkyl) X Ar 2 Ar (I-b) R'
11. 12 12 wherein Ar , Ar , m, A, n, R and R are as defined in claim 1 under hydrolytic conditions, in order to prepare a compound of the formulas NIL· Ar or c) ring closing a compound of the formula: Ar (I-a) - 90 ί 4 9 4 S 12 12 wherein Ar , Ar , m, A, n, R and R are as defined in claim 1 with an appropriate cyclizing agent by known methods in order to prepare a compound of the formula: (I-c) or wherein 1·Α is a hydrogen atom, a lower alkyl, phenyl, phenylmethyl, mercapto, amino, lover alkyloxycarbonylamino or cyeloalkyl group, by the reaction of (IV) with an 91 appropriate cyclizing agent, or 0' r~\ Ax X Ar 2 claim ,1 in order to prepare a compound of the formula: Ar (V) C Ar (I-c) or e) acylating an appropriate compound of the formula (I-a) above, by standardN-acylating procedures in order to prepare a compound of the 'formula: NH-CO-(lower alkyl) (I-e) * ·»· or f) introducing the group iA by known methods into a compound of the formula (I-c) above, in order to prepare a compound of the formula: wherein L is a lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl-lower alkyl, carboxy-lower alkyl, phenylmethyl, lower alkylaminocarbonyl, hydroxymethyl or lower alkenyl group, provided that the unsaturation in the lower alkenyl is located in a position other than ¢(, or g) condensing a compound of the formula: E-C II. -'·! n 2n (XVI) wherein B is as defined in claim 1 with an appropriate reactive ester of the formula: Ar 1 W-CH (XVII) o Ar*’ wherein Ar 1 and Ar 2 are as defined in claim 1 and W is defined hereinabove, in order to prepare a compound of the formula: ΛΛ / Ar n 2n N-CH .V_/ \ , 2 Ar (i-g) or h) preparing a compound of the formula: , , > S-(lower alkyl) by known S-alkylating procedures, starting from the corresponding -SH substituted analog; and, if desired, preparing pharmaceutically acceptable acid addition salts 5 of the products of steps a) to h), 12. A process as claimed in claim 11 wherein steps (a) and (g) are effected at an elevated temperature in the presence of a reaction-inert organic solvent and an appropriate base. ' 10
12. 13* A proces.s for preparing 1-f3-/~4-(diphenylmethyl)l-piperazinyl/propyl·^-1,3-dihydro-2H-benzimidazol-2-one which comprises reacting 1-(3-chloropropyl)-1,3-dihydro-2Hbenzimidazol-2-one with 1-(diphenylmethyl)piperazine.
13. 14. A process for preparing 1-/ 3-)4-/ bis(4-fluoro- 94 ti *· phony 1 )methy/7-l-piperaziny propyl?-1, j-dihydro-ailbenzinidazol-2-one which comprises reacting 1,3-dihydro1-(3-hydroxypropyl)-2II-benzimidazol-2-one methaneaulfonate with 1-/ bis(p-fluorophenyl)methy1/piperazine. 5 15. A process for preparing l-/ _ 4-^4-/ - bis(4-fluorophenyl)methyl7''l-piperazinyl^butyl/-l,3-dihydro-2H-ben2imida2ol“ 2-one which comprises reacting 1-(4-chlorobutyl)-1,3dihydro-2H-benzimidazol-2-one with 1-/ bis(p-fluorophenyl)methyjL/piperazine. 10 15. A process for preparing 1-^4-/ 4-(diphenylmethyl) l-piperazinyl/bucylj-l,3-dihydro-2H-benzimidazol-2-one which comprises reacting l-(4-chlorobutyl)-l,3-dihydro2H-benzimidazole-2-one with 1-(diphenylmethyl)piperazine.
14. 17· A process for preparing 1-^3-/ 4-(diphenylmethyl) 15 l-piperazinyl7propy^-ΙΗ-benzimidazole which comprises reacting 1-(3-chloropropyl)-ΙΗ-benzimidazole with 1(diphenylmethyl)Piperazine.
15. 18. A process for preparing 1-/ 4-14-/ (4-fluorok? phenyl)phenylmethyV-l-piperaziny/jbuty1/-Ih-bsnzimidazole 20 which comprises reacting 1-(4-chlorobutyl)-lH-benzimidazole with 1-/ - (4-fluorophenyl)phenylmethyl/piperazine.
16. 19. A process for preparing 1-/ 4-^4-/ bis(495 fluorophenyl)methyl7“l - piperazinyljbutyl7-lH-benzimidazole which comprises reacting 1-(4-chlorobutyl)-lH-benzimidasole with 1-/ bis(g-fluorophenyl)methyl/piperazine.
17. 20. A process for preparing a compound of formula I 2 as claimed in claim 1 substantially as hereinbefore described with reference to any one of the specific Examples.
18. 21. A compound of formula I whenever prepared by a process as claimed in any one of claims 11 to 20.
19. 22. A pharmaceutical composition which comprises at 10 least one compound as claimed in any one of claims 1 to 9 or 21, or a pharmaceutically acceptable salt as claimed in claim 10, together with a pharmaceutically acceptable diluent or carrier.
20. 23. A pharmaceutical composition as claimed in ic claim 22 which is in unit dosage form.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US67291976A | 1976-04-02 | 1976-04-02 | |
US75306276A | 1976-12-21 | 1976-12-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE44942L IE44942L (en) | 1977-10-02 |
IE44942B1 true IE44942B1 (en) | 1982-05-19 |
Family
ID=27100846
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE699/77A IE44942B1 (en) | 1976-04-02 | 1977-04-01 | Novel piperazine and piperidine derivatives |
Country Status (31)
Country | Link |
---|---|
JP (1) | JPS52122380A (en) |
AT (1) | AT357541B (en) |
AU (1) | AU515173B2 (en) |
BG (1) | BG36044A3 (en) |
CA (1) | CA1097646A (en) |
CH (1) | CH634317A5 (en) |
CS (1) | CS191337B2 (en) |
CY (1) | CY1210A (en) |
DE (1) | DE2714437A1 (en) |
DK (1) | DK153477C (en) |
EG (1) | EG12722A (en) |
ES (1) | ES456690A1 (en) |
FI (1) | FI66178C (en) |
FR (1) | FR2346350A1 (en) |
GB (1) | GB1579365A (en) |
GR (1) | GR62465B (en) |
HU (1) | HU179491B (en) |
IE (1) | IE44942B1 (en) |
IL (1) | IL51797A (en) |
IT (1) | IT1086841B (en) |
KE (1) | KE3338A (en) |
LU (1) | LU77052A1 (en) |
MY (1) | MY8400208A (en) |
NL (1) | NL190522C (en) |
NO (1) | NO146774C (en) |
NZ (1) | NZ183506A (en) |
PH (1) | PH12951A (en) |
PT (1) | PT66384B (en) |
SE (1) | SE431333B (en) |
SU (1) | SU683621A3 (en) |
YU (1) | YU39992B (en) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4181802A (en) * | 1978-05-11 | 1980-01-01 | Janssen Pharmaceutica N.V. | 1-(Heterocyclylalkyl)-1,3-dihydro-2-H-benzimidazole-2-ones |
US4254127A (en) * | 1980-04-03 | 1981-03-03 | Janssen Pharmaceutica, N.V. | 1,3-Dihydro-1-[(1-piperidinyl)alkyl]-2H-benzimidazol-2-one derivatives |
JPS57106663A (en) * | 1980-12-23 | 1982-07-02 | Kyorin Pharmaceut Co Ltd | 1,4-disubstituted piperazine derivative and its preparation |
ES8308553A1 (en) * | 1982-06-17 | 1983-09-01 | Ferrer Int | Piperazine derivatives, a process for preparing them and pharmaceutical compositions. |
DE3442757A1 (en) * | 1984-11-23 | 1986-05-28 | Wella Ag, 6100 Darmstadt | USE OF 2-NITROANILINE DERIVATIVES IN HAIR COLORING AGENTS AND NEW 2-NITROANILINE DERIVATIVES |
JPS625956A (en) * | 1985-07-02 | 1987-01-12 | Terumo Corp | Vinyl derivative and 5-lipoxygenase action inhibitor containing same |
FR2635524B1 (en) * | 1988-08-19 | 1992-04-24 | Adir | NOVEL BENZOPYRROLIDINONE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
US5169855A (en) * | 1990-03-28 | 1992-12-08 | Du Pont Merck Pharmaceutical Company | Piperidine ether derivatives as psychotropic drugs or plant fungicides |
IT1251144B (en) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | BENZIMIDAZOLONE DERIVATIVES |
ES2118255T3 (en) * | 1992-03-23 | 1998-09-16 | Janssen Pharmaceutica Nv | AGENT FOR USE AS AN ANTI-IRRITANT. |
EP0600318B1 (en) * | 1992-11-29 | 1998-04-08 | Clariant GmbH | Asymmetric, halogenated benzophenones and process for their preparation |
US5883094A (en) * | 1995-04-24 | 1999-03-16 | Pfizer Inc. | Benzimidazolone derivatives with central dopaminergic activity |
US5889010A (en) * | 1995-05-18 | 1999-03-30 | Pfizer Inc. | Benzimidazole derivatives having dopaminergic activity |
IT1292409B1 (en) * | 1997-06-24 | 1999-02-08 | Bidachem Spa | PROCEDURE FOR THE PREPARATION OF OXATOMIDE |
GB0009479D0 (en) * | 2000-04-17 | 2000-06-07 | Cipla Limited | Antihistaminic compounds |
CA2417081C (en) * | 2000-09-19 | 2008-08-05 | Enzo Cereda | New n, n'-disubstituted benzimidazolone derivatives with affinity at the serotonin and dopamine receptors |
WO2002060878A1 (en) * | 2001-01-30 | 2002-08-08 | Sumitomo Pharmaceuticals Co., Ltd. | Benzimidazolidinone derivatives |
EP1618105A1 (en) * | 2003-05-01 | 2006-01-25 | Vernalis Research Limited | Azetidinecarboxamide derivatives and their use in the treatment of cb1 receptor mediated disorders |
MY150958A (en) * | 2005-06-16 | 2014-03-31 | Astrazeneca Ab | Compounds for the treatment of multi-drug resistant bacterial infections |
US20100029681A1 (en) * | 2006-05-26 | 2010-02-04 | Hassan Pajouhesh | Heterocyclic compounds as calcium channel blockers |
WO2010128516A2 (en) * | 2009-05-04 | 2010-11-11 | Symed Labs Limited | Process for the preparation of flibanserin involving novel intermediates |
CN104926734B (en) * | 2015-07-07 | 2017-04-05 | 苏州立新制药有限公司 | The preparation method of flibanserin |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2882271A (en) * | 1959-04-14 | Xcixcxh | ||
US3362956A (en) * | 1965-08-19 | 1968-01-09 | Sterling Drug Inc | 1-[(heterocyclyl)-lower-alkyl]-4-substituted-piperazines |
US3369022A (en) * | 1966-11-07 | 1968-02-13 | Robins Co Inc A H | 3-piperazinoalkyl-2-benzoxazolinones |
JPS5070389A (en) * | 1973-10-30 | 1975-06-11 |
-
1977
- 1977-03-02 YU YU566/77A patent/YU39992B/en unknown
- 1977-03-04 NZ NZ183506A patent/NZ183506A/en unknown
- 1977-03-09 ES ES456690A patent/ES456690A1/en not_active Expired
- 1977-03-10 FR FR7707106A patent/FR2346350A1/en active Granted
- 1977-03-14 BG BG035664A patent/BG36044A3/en unknown
- 1977-03-14 GR GR52987A patent/GR62465B/en unknown
- 1977-03-18 CA CA274,240A patent/CA1097646A/en not_active Expired
- 1977-03-24 CS CS771972A patent/CS191337B2/en unknown
- 1977-03-25 GB GB12754/77A patent/GB1579365A/en not_active Expired
- 1977-03-25 CY CY1210A patent/CY1210A/en unknown
- 1977-03-30 EG EG180/77A patent/EG12722A/en active
- 1977-03-31 LU LU77052A patent/LU77052A1/xx unknown
- 1977-03-31 DE DE19772714437 patent/DE2714437A1/en active Granted
- 1977-03-31 JP JP3556077A patent/JPS52122380A/en active Granted
- 1977-03-31 IT IT48768/77A patent/IT1086841B/en active
- 1977-03-31 IL IL51797A patent/IL51797A/en unknown
- 1977-03-31 AU AU23824/77A patent/AU515173B2/en not_active Expired
- 1977-04-01 SE SE7703842A patent/SE431333B/en not_active IP Right Cessation
- 1977-04-01 NL NLAANVRAGE7703564,A patent/NL190522C/en not_active IP Right Cessation
- 1977-04-01 DK DK145977A patent/DK153477C/en not_active IP Right Cessation
- 1977-04-01 FI FI771020A patent/FI66178C/en not_active IP Right Cessation
- 1977-04-01 IE IE699/77A patent/IE44942B1/en not_active IP Right Cessation
- 1977-04-01 PH PH19620A patent/PH12951A/en unknown
- 1977-04-01 AT AT230477A patent/AT357541B/en not_active IP Right Cessation
- 1977-04-01 CH CH415477A patent/CH634317A5/en not_active IP Right Cessation
- 1977-04-01 PT PT66384A patent/PT66384B/en unknown
- 1977-04-01 HU HU77JA782A patent/HU179491B/en unknown
- 1977-04-01 SU SU772468056A patent/SU683621A3/en active
- 1977-04-01 NO NO771168A patent/NO146774C/en unknown
-
1983
- 1983-10-24 KE KE3338A patent/KE3338A/en unknown
-
1984
- 1984-12-30 MY MY208/84A patent/MY8400208A/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
IE44942B1 (en) | Novel piperazine and piperidine derivatives | |
US4200641A (en) | 1-[(Heterocyclyl)-alkyl]-4-diarylmethoxy piperidine derivatives | |
US4250176A (en) | Piperazine derivatives | |
EP0005318B1 (en) | N-heterocyclyl-4-piperidinamines, methods for their preparation, pharmaceutical compositions comprising them, intermediates therefor, and method for the preparation of the intermediates | |
US3209006A (en) | Phenylpiperidine and phenyltetrahydropyridine compounds | |
US3717655A (en) | 1-(beta-aryl)ethyl-imidazole derivatives | |
EP0037713B1 (en) | Novel 1,3-dihydro-1-((1-piperidinyl)alkyl)-2h-benzimidazol-2-one derivatives | |
NZ200935A (en) | N-aryl-piperazine alkanamides and pharmaceutical compositions | |
NL8201021A (en) | 2-PHENOXYALKYL-1,2,4-TRIAZOL-3-ON COMPOUNDS AND DERIVATIVES THEREOF WITH ANTIDEPRESSIVE ACTION; METHOD FOR PREPARING THEREOF PHARMACEUTICAL PREPARATIONS; METHOD FOR TREATING DEPRESSION IN MAMMALS | |
JPS6193183A (en) | Novel 1-(benzoazolylalkyl)piperidine derivative | |
SK31793A3 (en) | Pyridine and pyridine n-oxide derivatives of diaryl methyl piperidines and piperazines and compositions and methods of use thereof | |
US4179505A (en) | 5-[4-(Diarylmethyl)-1-piperazinylalkyl]benzimidazole derivatives | |
CA1246074A (en) | Derivatives of hydroxy- or amino-substituted (piperidinylalkyl)quinazolines | |
FI62667C (en) | FOERFARANDE FOER FRAMSTAELLNING AV ANTIEMETISKA 1- (BENZAZOLYLALKYL) PIPERIDINDERIVAT | |
DK151801B (en) | ANALOGY PROCEDURE FOR PREPARING 1- (BENZIMIDAZOLYL PROPYL) -4-SUBSTITUTED PIPERIDE INGREDIENTS | |
US4338330A (en) | Benzimidazole derivatives, their use, and compositions containing these derivatives | |
NZ227801A (en) | Azolylmethyl benzimidazole carbamates and anthelmintic compositions | |
US3842090A (en) | Certain 1-aminomethyl-6-phenyl 4h-s-triazolo(4,3-a)(1,4)benzodiazepines | |
IE49526B1 (en) | Phenyl piperazine derivatives,their preparation and antiagressive medicines containing them | |
US3781289A (en) | 7-chloro-1-methyl-5-phenyl-s-triazolo (4,3-a)quinolines | |
JPS615068A (en) | Piperazine and piperidine derivative | |
DE60000500T2 (en) | SUBSTITUTED N- (PIPERIDIN-4-YL) -4H-3,1-BENZO (THIA / OXA) ZIN-2-AMINE, THEIR PRODUCTION AND THERAPEUTIC USE | |
DE2804416A1 (en) | NEW PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS | |
KR800000491B1 (en) | Process for preparing 1-benzazolylalyl-4-substituted-piperidines | |
US3431274A (en) | 1-phenylbenzimidazole-2-methanol |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MK9A | Patent expired |