AU6983094A - Tetrazole derivatives having antihistaminic and antiallergic activity - Google Patents
Tetrazole derivatives having antihistaminic and antiallergic activityInfo
- Publication number
- AU6983094A AU6983094A AU69830/94A AU6983094A AU6983094A AU 6983094 A AU6983094 A AU 6983094A AU 69830/94 A AU69830/94 A AU 69830/94A AU 6983094 A AU6983094 A AU 6983094A AU 6983094 A AU6983094 A AU 6983094A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- atom
- tetrazol
- piperidine
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000003536 tetrazoles Chemical class 0.000 title claims description 11
- 239000000739 antihistaminic agent Substances 0.000 title claims description 10
- 230000001387 anti-histamine Effects 0.000 title claims description 9
- 230000003266 anti-allergic effect Effects 0.000 title description 9
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 208000006673 asthma Diseases 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 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 claims description 4
- 239000000043 antiallergic agent Substances 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 58
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 14
- 238000000921 elemental analysis Methods 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229940093499 ethyl acetate Drugs 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- 206010006482 Bronchospasm Diseases 0.000 description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 230000007885 bronchoconstriction Effects 0.000 description 7
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 6
- -1 phenyl magnesium halide Chemical class 0.000 description 6
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 5
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- 230000000881 depressing effect Effects 0.000 description 5
- 239000012530 fluid Substances 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229940126208 compound 22 Drugs 0.000 description 4
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- 238000000354 decomposition reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
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- 229920000609 methyl cellulose Polymers 0.000 description 4
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- 235000010981 methylcellulose Nutrition 0.000 description 4
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- 229940092253 ovalbumin Drugs 0.000 description 4
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 3
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- 241000700198 Cavia Species 0.000 description 3
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 3
- 206010010071 Coma Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229960001803 cetirizine Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229960002698 oxatomide Drugs 0.000 description 3
- BAINIUMDFURPJM-UHFFFAOYSA-N oxatomide Chemical compound O=C1NC2=CC=CC=C2N1CCCN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 BAINIUMDFURPJM-UHFFFAOYSA-N 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IAWGOEKOSDXULX-UHFFFAOYSA-N 1-(6,11-dihydrobenzo[c][1]benzoxepin-11-yl)-4-[3-(2H-tetrazol-5-yl)propyl]piperazine Chemical compound C1=CC=CC=2OCC3=C(C(C21)N2CCN(CC2)CCCC2=NN=NN2)C=CC=C3 IAWGOEKOSDXULX-UHFFFAOYSA-N 0.000 description 2
- IZLRTTAYGQOVLW-UHFFFAOYSA-N 1-(6,11-dihydrobenzo[c][1]benzoxepin-11-yl)-4-[4-(2H-tetrazol-5-yl)butyl]piperazine Chemical compound C1=CC=CC=2OCC3=C(C(C21)N2CCN(CC2)CCCCC2=NN=NN2)C=CC=C3 IZLRTTAYGQOVLW-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
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- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical class C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- CMVAYPJYRXHDOB-UHFFFAOYSA-N ethyl 2-oxopiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCCCC1=O CMVAYPJYRXHDOB-UHFFFAOYSA-N 0.000 description 1
- 229960003699 evans blue Drugs 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
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- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- REEUVFCVXKWOFE-UHFFFAOYSA-K gallamine triethiodide Chemical compound [I-].[I-].[I-].CC[N+](CC)(CC)CCOC1=CC=CC(OCC[N+](CC)(CC)CC)=C1OCC[N+](CC)(CC)CC REEUVFCVXKWOFE-UHFFFAOYSA-K 0.000 description 1
- 229960005271 gallamine triethiodide Drugs 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- JUINSXZKUKVTMD-UHFFFAOYSA-N hydrogen azide Chemical compound N=[N+]=[N-] JUINSXZKUKVTMD-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
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- 210000004072 lung Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 210000001616 monocyte Anatomy 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- NVTNQIBQPLGHGE-UHFFFAOYSA-N n,n-dibutylbutan-1-amine;hydrate Chemical compound [OH-].CCCC[NH+](CCCC)CCCC NVTNQIBQPLGHGE-UHFFFAOYSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical class [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000037321 sleepiness Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
DESCRIPTION
TETRAZOLE DERIVATIVES HAVING ANTIHISTAMINIC AND ANTIALLERGIC ACTIVITY BACKGROUND OF THE INVENTION:
This invention relates to novel tetrazole derivatives or salts thereof, as well as antihistamines, antiallergic agents and asthma treating agents that contain the novel tetrazole derivatives or salts thereof and which exhibit satisfactory antihistaminic and antiallergic actions while causing less central nervous system depressing effects. The compounds of the invention are also effective in the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.
A number of benzhydryl derivatives have heretofore been synthesized and their various pharmacological actions including antiallergic action are under review. European Patent No. 82-870006 and Japanese Patent Public Disclosure (Kokai) No. Hei 3-246287 teach certain kinds of carboxylic acid derivatives, and WO 93/02062 teaches certain kinds of tetrazole derivatives. Japanese Patent Public Disclosure (Kokai) Nos. Hei 4-234359 and 4-234387 teach piperazine derivatives. However, these compounds have been unsatisfactory in that their efficacy is insufficient or that they cause central nervous system depressing effects such as sleepiness and sedation. It should also be mentioned that the prior art compounds are capable of suppressing the early-phase reaction in asthma but their ability to suppress the late-phase reaction has been insufficient. Under the circumstances, steroids are currently used in the treatment of asthma of the late-phase reaction type but steroids have their own problems, namely, those of side effects. Conventional antihistamines also have had defects, one of which is that they have anticholinergic actions causing side effects such as thirst and ydriasis. With a view to solving these problems, various studies have so far been conducted but the results have not been completely satisfactory.
SUMMARY OF THE INVENTION:
An object, therefore, of the present invention is to provide compounds that exhibit more satisfactory antiallergic and antihistaminic actions, that are effective against both early- and late-phase reaction in asthma and which yet are highly safe in use.
Under the circumstances described above in connection with the prior art, the present inventors synthesized many tetrazole derivatives and reviewed their antihistaminic, antiallergic and central nervous system depressing actions. Surprisingly enough, they found that tetrazole derivatives of the general formula (1) to be defined below or salts thereof exhibited satisfactory antihistaminic and antiallergic actions and that, in addition, those derivatives or salts thereof were as effective as steroids in suppressing the late-phase reaction in asthma, while causing only weak central nervous system depressing effects. The present invention has been accomplished on the basis of this finding. The present invention, in its first aspect, provides tetrazole derivatives of the general formula(l):
(where A represents -CH=CH- , -CH2-CH2-, -CH20-, and oxygen atom or a sulfur atom or in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together
with Z or represents a hydroxyl group, or (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively; p represents an integer of 2 or 3; and n represents an integer of 1 - 6) or pharmacologically acceptable salts thereof.
In its second aspect, the invention provides an antihistamine, an antiallergic agent and an asthma treating agent that contain those tetrazole derivatives or pharmacologically acceptable salts thereof as effective ingredients. DETAILED DESCRIPTION OF THE INVENTION:
Some of the compounds of the present invention have optical isomers and in that case the invention encompasses all applicable isomers.
Salts of the compounds of the invention are any medicinally acceptable salts that are exemplified by, but in no way limited to, addition salts of acids including hydrochloric acid, nitric acid, sulfuric acid, maleic acid, fumaric acid, oxalic acid, citric acid, hydrobromic acid, tartaric acid, succinic acid, sulfamic acid, mandelic acid, malonic acid and phosphoric acid, as well as basic salts including sodium salts, potassium salts, lithium salts, calcium salts and zinc salts. Compounds (1) of the invention may be produced by the following reaction scheme 1) :
(where V, W, X, Y, Z, p, n, A and B have the same meanings as defined above, and L represents a halogen atom). In this step, the compounds represented by the general formula (2) are reacted with compounds of the general formula (4) in the presence of bases to prepare compounds represented by the general formula (3). The reaction is preferably carried out in inert solvents. Exemplary solvents include:water; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; others such as acetonitrile, dimethyl sulfoxide and dimethylformamide. These solvents may be used either independently or in combination. The reaction temperature varies with the starting materials to be used but the range from 0 to 200*C may typically be adopted. Base catalysts are generally effective for but by no means indispensable to the progress of the
reaction. Preferred bases include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethyla ine, pyridine and tributylammonium hydroxide. Compounds of the general formula (3) may further be reacted with trialkyltin azide or trialkylsilye azide; alternatively, the compounds may be reacted with metal salts of hydrogen azide such as sodium azide or potassium azide in the presence of ammonium salts. This reaction is preferably carried out in inert solvents such as xylene, toluene, benzene, tetrahydrofuran, dioxane, dimethylfor- mamide and N-methylpyrrolidone, which may be used either independently or in combination. The reaction temperature varies with the starting materials to be used but the range from 0 to 200 °C may typically be adopted.
Compounds represented by the structural formula (2) are either known or synthesizable by reaction in accordance with one of the following schemes 2) , 3) or 4) : 2)
Conversion from (5) to (6) can be accomplished by causing a substituted phenyl magnesium halide or substituted phenyl lithium to act on (5). Conversion from (6) to (7) can be accomplished by causing a catalyst (e.g. platinum oxide, palladium on carbon, or palladium) to act In hydrogen at either atmospheric or superatmospheric pressure. Conversion from (7) to (2a) can readily be accomplished either under acidic conditions (e.g. acetic acid-sulfurlc acid) or under ordinary dehydrative reactive conditions (e.g. toluenesulfonlc acid-benzene).
)
Conversion from (9) to (10) can be accomplished by using titanium in a lower oxidation state. Any inert solvents may be used and preferred examples are ethereal solvents such as dioxane, tetrahydrofuran, dimethoxyethane and ether. 4)
Conversion from (8) to (12) can be accomplished by known methods. Conversion from (12) to (13) can readily be accomplished either under acidic conditions (e.g. acetic acid-sulfuric acid) or under ordinary dehydrative reaction conditions (e.g. toluenesulfonic acid-benzene). Conversion from (13) to (2b) can be accomplished by first causing an alkyl chloroformate to act on (13) to form a carbamate and then hydrolyzing it with an alkali.
Specific examples of the compounds of the present invention are listed below. Compound 1: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[3-(lH-tetrazole-5- yl)propyl]piperidine Compound 2: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-(lH-tetrazol-5- ylmethyl)piperidine
Compound 3: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[4-(lH-tetrazol-5-yl)- butyl]piperidine Compound 4:
4-(10,ll-Dihydrodibenzo[a,d]cyclohepten-5-ylidene)-1-[3-(1H- tetrazol-5-yl)propyl]piperidine
Compound 5: 4-(6H-Dibenzo[b,e]oxepin-ll-ylidene)-l-[3-(lH-tetrazol-5- yl)-propyl]piperidine Compound 6: 4-[Bis(4-fluorophenyl)methylene]-l-[3-(lH-tetrazol-5- yDpropyl]piperidine Compound 7: 4-(phenyl-2-thienylmethylene)-l-[3-(lH-tetrazol-5- yl)propyl]piperidine
Compound 8: 4-Benzhydrylylidene-l-[3-(lH-tetrazol-5-yl)propyl]piperidine
Compound 9: 4-Benzhydrylylidene-l-[5-(III-tetrazol-5-yl)pentyl]piperidine
Compound 10: α,α-Dlphenyl-N-[3-(lH-te razol-5-yl)propyl]piperidin-4- ylmethanol
Compound 11: 4-[Bis(4-methoxyphenyl)methylene]-l-[4-(lH-tetrazol-5- yl)butyl]piperidine
Compound 12: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[5-(lH-tetrazol-5- yl)pentyl]piperidine
Compound 13: 4-Xanthen-9-ylidene-l-[3-(lH-tetrazol-5-yl)propyl]piperidine
Compound 14: 4-Thioxanthen-9-ylidene-l-[3-(lH-tetrazol-5- yDpropyl]piperidine
Compound 15: l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]piperazine
Compound 16: l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-[1,4]diazepan
Compound 17: l-Benzhydryl-4-(lH-tetrazol-5-ylmethyl)piperazine
Compound 18: l-Benzhydryl-4-[4-(lH-tetrazol-5-yl)butyl]piperazine Compound 19:
1-[ (4-chlorophenyl)phenylmethyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine
Compound 20: l-[Bis(4-fluorophenyl)methyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine
Compound 21: 4-Benzhydryloxy-l-[3-(lH-tetrazol-5-yl)propyl]-piperidine
Compound 22: 4-[ (4-chlorophenyl)phenylmethoxy]-l-[3-(lH-tetrazol-5- yl)propyl]piperidine
Compound 23: 4-[Bis(4-fluorophenyl)methoxy]-l-[3-(III-tetrazol-5- yDpropyl]piperidine
Compound 24: 4-[ (4-chlorophenyl)phenylmethoxy]-l-[4-(lH-tetrazol-5- yl)butyl]piperidine
Compound 25: 4-(Phenyl-p-chlorophenylmethylene)-1-[3-(lH-tetrazol-5- yDpropyl]piperidine Compound 26: 4-(10,ll-Dihydrodibenzo[a,d]cycloheptan-5-yl)-l-[3-(lH- tetrazol-5-yl)propyl]piperazine
Compound 27: 4-(10,11-Dihydrodibenzo[a,d]cycloheptan-5-yl)-1-[4-(1H- tetrazol-5-yl)butyl]piperazine Compound 28:
4-(6H-Dibenzo[b,e]oxepin-ll-yl)-1-[3-(lH-tetrazol-5- yl)propyl]piperazine
Compound 29: 4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[3-(lH-tetrazol-5- yl)propyl]piperidine Compound 30: 4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[4-(lH-tetrazol-5- yl)butyl]piperidine Compound 31: 4-(6H-Dibenzo[b,e]oxepin-ll-yl)-1-[4-(lH-tetrazol-5- yl)butyl]piperazine
Compound 32: 4-[ (4-Chlorophenyl)phenylmethylene]-l-[4-(lH-tetrazol-5- yl)butyl]piperidine Compound 33:
4-[ (4-Chlorophenyl)phenylmethylene]-1-[3-(1H-tetrazol-5- yDpropyl]piperidine
The compounds of the invention or pharmacologically acceptable salts thereof may be formulated for peroral or parenteral administration by mixing them with adjuvants that are acceptable in pharmaceutical formulation procedures.
Solid pharmaceutical formulations for peroral administration include tablets, powders, granules and capsules and these can be produced by combining the compound (1) of the invention with suitable additives such as exciplents (e.g. lactose, mannitol, corn starch and crystalline cellulose), binders (e.g. cellulose derivatives, gum arable and gelatin), disintegrators
(e.g. carboxymethyl cellulose calcium), and lubricants (e.g. talc and magnesium stearate). If desired, these solid preparations may be formulated as enteric drugs by coating with bases such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate and methacrylate copolymer. Liquids for peroral administration may be exemplified by emulsions, solutions, suspensions, syrups and elixirs and these can be produced by combining the compound (1) of the invention with commonly employed inert diluents such as purified water and ethanol. In addition to inert diluents, the resulting compositions may contain adjuvants (e.g. wetting agents or suspending agents), sweeteners, flavoring agents, fragrances and antiseptics. Other applicable dosage forms are aerosols that can be produced by known methods.
Pharmaceutical preparations for parenteral administration include liquids for injection and they can be produced by combining the compound (1) of the invention with water, ethanol, glycerin, common surfactants, etc. Other parenteral dosage forms include inhalers, liquids for external application, eye drops, nasal solutions and liniments such as ointments.
The dosage of the compound (1) of the invention depends on various factors including age, body weight, the severity of the disease, the efficacy in treatment, the method of administration and the period of administra¬ tion. Typically, the compounds are administered perorally one to three times a day at doses of 1 - 500 mg, preferably 5 - 50 mg. Alternatively, they may be administered parenterally one to several times a day at doses of 0.1 - 500 mg.
The pharmacological actions of representative examples of the compound (1) and salts thereof are described below.
Test 1: Histamine Hi-receptor antagonism in vitro
Trachea were removed from Male Hartley guinea-pigs (300 - 600g) and cut into strips. The tissues were suspended in 20-ml jacketed organ baths containing Tyrode physiological solution, aerated with 95% 02 : 5% C02 and maintained at 37°C. Changes in isometric tension were measured with a force-displacement transducer and recorded on a polygraph. The preparations were placed under 1 g of passive tension and allowed to equilibrate for 30 - 60 min. The efficacy of test compounds on histamine(10"5 M)-induced constriction was calculated and expressed as Inhibitory concentration of 50% (IC50). The data obtained are shown in Table 1.
Cetirizine (see Japanese Patent Public Disclosure No. Sho 57-149282) used as a control had an IC5o of 2.40 μM.
Table 1
Compounds ICso (μM) compound 1 0.08 compound 5 0.04 compound 15 0.07 compound 20 0.08 compound 21 0.01 oxatomide 0.13 diphenhydramin 0.3 ketotlfene 0.08
Test 2: Antiallergic effect(s)
Passive cutaneous anaphylaxis (PCA) in rats: Male SD rats were sensitized intradermally on their shaved backs with 0.1 ml of appropriately diluted homologous anti-serum containing anti-dinitrophenyl conjugated Ascaris (DNP-As). Forty eight hours later, the rats were challenged with 1 ml of saline containing 300 μg of DNP-As and 5 μg of Evans blue. Thirty minutes after the challenge, the rats were killed, and the skin of the back was removed. The severity of PCA was assessed by measuring the dye exudate Into the
skin according to the method of Harada (Japanese Journal of Allergology, 15,1). Test compounds were suspended in 0.5% methyl cellulose in saline and administered (p.o.) before 60 min. of the challenge. The data of inhibiting PCA was expressed by the amount of dye exudate on the site (Table 2) .
Table 2
Compounds Inhibition(%) compound 1 99 compound 7 99 compound 19 70 compound 20 81 compound 21 80 compound 22 79 compound 25 71 ketotifene 99 oxatomide 53
Test 3: Acute toxicity
Groups of 4 - 5 wk-old ICR mice were used, each group consisting of 5 animals. Each compound was suspended in 0.5% methyl cellulose in saline and administered 100 mg/Kg (i.p.). Observation was made for 7 days. No animals administered the test compounds were dead at this dosage, but diphenhydramin was lethal at 100 mg/Kg. Test 4: Effect on Pentobarbital Induced Sleep Groups of 4 or 5 wk-old ICR mice were used, each group consisting of 10 animals.
Each of the test compounds was suspended in 0.5% methyl cellulose solution and administered orally at a dose of 25 mg/Kg. One hour later, pentobarbital was injected intraperitoneally at a dose of 40 mg/Kg to induce coma. The moment the animal lost the righting reflex to lie on the back was regarded the start of coma and the
moment it recovered the righting reflex was regarded as the end of coma.
Terfenadine was used as a control compound, which is a known antiallergic agent that is not a strong sleep inducer. The data obtained are shown in Table 3 as the percent increase in sleep time compared to the negative control group (given no compounds) .
Table 3
Compounds Increase in Sleep Time (%)
Terfenadine + 44
Compound 3 - 9
Compound 6 + 4
Compound 20 - 31
Thus, the invention compounds were verified to have a smaller central nervous system depressing action. Test 5: Inhibitory effects on leukocytes recruited into Guinea-pig broncoalveolar lavage fluid This experiment was conducted according to the methods described in America Review of Respiratory Disease, 1990,142,680-685. Male Hartley Guinea-pig (5 weeks old) was passively sensitized with injection of 0.25 ml of anti-ovalbumin (raised in rabbit). Forty eight hours later the animals were treated with mepyramin (an Hi- receptor antagonist, i.p.) in order to avoid anaphylactic death, then applied to plastic exposure-chamber connected with ultrasonic nebulizer, where 0.25% ovalbumin in saline was inhalated for 10 in. Twenty four hours later, the treated guinea-pigs were administered overdose of pentobarbital, and lung were lavaged with 25 ml of phosphate buffered saline (pH 7.4) through a polyethylene tube introduced through tracheostomy. Total cells in the lavage fluid were counted by Coulter Counter, and differential cell counts were determined from cytospun preparations and stained by May-Gruenwald Giemza stain.
Cells were identified as macrophage , neutrophils, eosinophils and lymphocytes by standard morphology, and absolute number of each cell type were calculated. Each compound suspended in 0.5% methyl cellulose containing 0.05% Tween 80 was administered (30 mg/Kg, p.o.) two times (1 hour before and 6 hours after ovalbumin-challenge) Inhibition of recruitment of leukocytes into lavage fluid were expressed;
Inhibition (%)
(cells in treated animals) (cells in non-challenged animals (cells in non-treated animals) (cells in non-challenged animals) x 100
In these series of experiments, the compounds tested showed the efficacy to inhibiting the recruitment of leukocytes into bronchoalveolar fluid; showing the ability to employ to allergic late phase reactions. In contrast, oxatomide, ketotifene and diphenyldramin showed no inhibitory effects on this experiment. Cetirizine had weak effects as noted below.
Table 4
Inhibition (%)
Compounds Eosinophils ophils Monocyte compound 22 69 46 14 compound 19 53 67 63 compound 21 60 20 25 compound 26 29 73 84 compound 6 28 70 79 compound 20 52 67 0 cetirizine 15 10 8
Test 6: Anti-Anaphylactic Bronchoconstriction
Bronchoconstriction was measured by the overflow technique of Konzett and Roessler. Male guinea-pigs (5 weeks, 300-350 g) were passively sensitized by an injection with anti-ovalbumin rabbit serum (0.1 ml/animal, i.v.). Two days later, the animals were anesthetized with urethane (1.5 g/Kg; i.p.). The trachea was canulated. for artificial ventilation. The right jagular vein was canulated for administration of test compound and antigen. Spontaneous respiration was abolished by gallamine triethiodide (5 mg/Kg) . The animals were artificially ventilated at 60 strokes per minute (stroke volume of 10 ml/Kg) . Bronchoconstriction was measured as the volume of inspiration overflow using a Ugo Bassile 7020 bronchospasm transducer. The compounds (1 mg/Kg) were administered intravenously 15 min. before antigen challenge In control group, vehicle alone was administered instead of the compounds.
The guinea-pigs were challenged with intravenous administration of ovalbumin (0.1 mg/Kg), then changes in the overflow volume were recorded for 30 min. Bronchoconstriction was represented as, (1) the peak height and (2) the area under the curve (AUC) of each trace. Percent inhibition of bronchoconstriction Is then calculated in terms of the peak height or the AUC as follows;
Increase in V (control group) - Increase in V (test group) Increase in V (control group) x 100
where V means "Bronchoconstriction represented as peak hight or AUC"
Table 5
Inhibition (peak height, %) Inhibition (AUC, %) compound 22 35 52 compound 21 53 59 centilizine 20 19
Example 62 18 16 (WO 93/02062)
The results of Tests 1 - 6 show that the compounds of the invention had satisfactory antihistaminic and antiallergic effects and proved to be significantly effective against both late- and early-phase reactions in asthma. It should particularly be noted that compounds 21 and 22 at the most preferred since they are potent suppressors of not only bronchoconstriction which occurs at the early phase of asthma but also the recruitment of leukocytes into bronchoalveolar fluid which occurs at the late stage of asthma. In view of these pharmacological effects they have, the compounds of the invention are also useful for the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.
The following examples are provided for the purpose of further illustrating the present invention but are in no way to be taken as limiting.
Example 1
4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[3-(lH-tetrazol-5- yl)propyl]piperidine:
4-Dibenzo[a,d]cyclohepten-5-ylidenepiperidine (5 g, 18.3 mmol), bromobutyronitrile (2.7 g, 18.3 mol) and potassium carbonate (10 g) were suspended in DMF and stirred at 100 βC for 3 h. The reaction solution was poured into water, subjected to extraction with ether, dried and concentrated under vacuum to yield an oil of 4-(4-di-benzo[a,d]cyclohepten-5-ylidenepiperidin-l- yl)butyronitrile. IR(nujol): cm"1: 2250, 1490, 1435, 1135
Without further purification, sodium azide (5.9 g, 0.92 mmol) and ammonium chloride (4.9 g, 0.92 mmol) were added to the compound and the mixture was stirred overnight at 110βC. The stirred reaction mixture was poured into water, adjusted to a pH of 6, subjected to extraction with chloroform, dried and concentrated under vacuum to an approximate volume of 30 ml. The concentrate was left to stand and the precipitating crystals were collected to yield the titled compound as a powder, m.p. (with decomposition): 134 - 139βC Elemental analysis for C2 H25Ns•2H20
C H N
Cal ' d 68.71 6.97 16.69
Found 69.08 7.21 16.85 MS(m/z): 384 (M+H) , (SIMS)
IR(nujol): cm"1: 1300, 1160, 1080, 990, 960, 950, 880 NMR(DMS0-d6) δppm: 7.37: (4H,m) , 7.28 (2H,d,J=7.3) , 6.96 (2H.s), 2,85 (2H,t,J=7.2) , 2.66 (2H,t,J=7.2) , 2.46 (2H,m), 2,27 (4H,m), 2.01 (2H,m), 1.86 (2H,m)
Example 2
4-Dibenzo [ a , d ] cyclohepten-5-ylidene-l ( lH-tetrazol-5- ylmethyD piperidine :
4-Dibenzo[a,d]cyclohepten-5-ylidenepiperidine (3.8 g. 14 mmol), bromoacetonitrile (1.68 g, 14 mmol) and potassium carbonate (5.5 g) were suspended in DMF and stirred at 100 βC for 3 h. The reaction solution was poured into water, subjected to extraction with ether, dried and concentrated under vacuum to yield an oil of 4-(4-dibenzo[a,d]cyclohepten-5-ylidenepiperidin-l-yl)- acetonitrile. Without further refining, sodium azide (2.99 g, 40.2 mmol) and triethylammonium chloride (2,77 g, 20.1 mmol) were added to the compound and the mixture was stirred in methylpyrrolidone (50 ml) for 3 h at 150 °C. The stirred reaction mixture was poured into water and adjusted to a pH of 6, subjected to extraction with chloroform, dried and concentrated under vacuum. The residue was subjected to silica gel chromatography and crystallized from ethyl acetate, yielding the titled compound in an amount of 3.19 g (62%). m.p. : 231 - 233βC MS(m/z): 356(M+H), 277, 185 IR(nujol): cm"1: 1630, 1305, 1270, 1160, 1025, 950
Similar procedures were taken in Examples 3 to 14 to synthesize the titled compounds.
Example 3
4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[4-(lH-tetrazol-5- yl)butyl]piperidine:
Foam
MS ( m/z ) : 398 ( M+H ) , 286 , 185 ( SIMS )
IR(nujol): cm"1: 1650, 1550, 1300, 1250, 950, 800, 760
NMR(DMS0-d6) δppm: 7.49 (4H,m), 7.40 (2H,m), 7.31
(2H,d,J=8.3) , 7.08 (2H,s), 2.95 (2H,t,J=7.2) , 2.71
(2H,t,J=7.2) , 2.49 (2H,t,J=6.9) , 2.37 (4H,m), 2.12 (2H,m),
1.77 (2H,m) , 1.58 (2H,m)
Example 4
4-(10,ll-Dihydrodibenzo[a,d]cyclohepten-5-ylidene)-l-[3-(lH- tetrazol-5-yl)propyl]piperidine:
Foam
MS(m/z): 386 (M+H) . (SIMS)
IR(nujol): cm"1: 1640, 1295, 950, 750
NMR(DMSO-de) δppm: 7.0 - 7.4 (8H,m), 4.03 (lH.s) 3,89
(2H,m), 2,85 (2H,t,J=7), 2.72 (2H,m), 2.44 (4H,m) 1,84
(2H,quintet,J=7)
Example 5
4-(6H-Dibenzo[b,e]oxepin-ll-ylidene)-l-[3-(lH-tetrazol-5- yDpropyl]piperidine:
1350
-20- m.p. (with decomposition): 192 - 196 βC
MS(m/z): 388 (M+H) , 290 (SIMS)
IR(nujol): cm"1: 2700, 1550, 1290, 1220, 760
NMR(DMS0-d6) δppm: 7.50 (lH,d,J=6), 7.35 (2H,m), 7.0-7.3
(3H,m), 6,84 (lH,t,J=7), 6.73 (lH,d,J=7), 3.1-3.6 (6H,m)
2.99 (4H,m), 2.88 (2H,m) , 2.79 (2H,m), 2.13 (2H, quintet,
J=7)
Example 6
4-[Bis(4-fluorophenyl)methylene]-l-[3-(lH-tetrazol-5- yDpropyl)piperidine:
Colorless powder m.p.: 185 - 187βC (from ethyl acetate)
MS(m/z): 396(M+H) . 298, 106 (SIMS)
IR(nujol): cm"1: 1600, 1500, 1450, 1410, 1220, 1160, 840
NMR(DMS0-d6) δppm: 7.21 (8H,m), 2.96 (2H, t ,J=7.3) , 2.68
(4H,t,J=5.3) , 2.59 (4H,t,J=2.0) , 2.35 (2H, t,J=5.3) , 1.98
(2H,m)
Example 7
4-(Phenyl-2-thienylmethylene)-l-[3-(lH-tetrazol-5- yl)propyl]piperidine:
m . p . : 215 - 219 °C
MS (m/z ) : 366 (M+H) , 268 ( SIMS )
IR(nujol): cπr : 1405, 1340, 1080, 970, 830, 705
NMR(DMS0-d6) δppm: 7.57 (IH,dd,J=l.0,5.3) , 7.43 (3H,m),
7.26 (2H,m), 7.12 (IH,dd,J=4.9,3.3) , 6.97 (lH.m), 3.00
(2H,t.J=7.2) , 2.62 (8H,m), 2.35 (2H,t,J=5.3) , 2.00 (2H,m)
Example 8
4-Benzhydrylylidene-l-[3-(lH-tetrazol-5- yl)proρyl]piperidine:
Colorless powder m.p.: 223 - 226 °C (from ethyl acetate)
MS(m/z): 360(M+H), 262, (SIMS)
IR(nujol): cm"1: 1600. 1500, 1450, 1410, 1220, 1160, 840
NMR(DMS0-d6) δppm: 7.21 (lOH.m), 2.96 (2H,t,J=7.3) ,
2.68(4H,t,J=5.3) , 2.59 (4H,t,J=2.0) , 2.35 (2H,t,J=5.3) , 1.98
(2H,m)
Example 9
4-Benzhydrylylidene-l-[5-(lH-tetrazol-5- yDpentyl]piperidine:
Foam
MS ( m/z ) : 388 ( M+H ) , ( SIMS )
IR(nujol): cffl-»: 1600, 1500, 1450, 1410, 1220, 1160, 840
NMR(DMSO-de) δppm: 7.2-7.6 (lOH.m), 3.01 (2H,t,J=7), 2,81
(4H,t,J=7), 2.64(4H,m), 2.48 (2H,m), 1.86 (2H,quintet,J=7) ,
1.66 (2H,quintet,J=7) , 1.48 (2H,quintet,J=7)
Example 10 α,α-Diphenyl-N-[3-(lH-tetrazol-5-yl)propyl]piperidin-4-yl- methanol:
m.p. (with decomposition ) ≥ 250 °C
MS(m/z): 378(M+H) , 133, 105
IR(nujol): cm"1: 1660, 1170, 1100, 1060
NMR(DMS0-d6) δppm: 7.51 (4H,d,J=7.6) , 7.27 (4H, t,J=6.9) ,
7.14 (2H,dd,J=7.6,6.9) , 3.20 (2H,d,J=ll .2) , 2.79 (4H,m),
2.50 (8H,m) , 1.92 (2H,m), 1.63 (lH.m) , 1.35 (2H,d,J=12.6)
Example 11
4-[Bis(4-methoxyphenyl)methylene]-l-[4-(lH-tetrazol-5- yl)butyl]-piperidine:
H
m.p. : 120 - 123 °C
MS(m/z): 434(M+H), 322, 121
NMR(DMS0-d6) δppra: 6.95 (4H, d, J=8.6) , 6.85 (4H, d, J=8.6) ,
3.72 (6H,s), 2.84 ( 2H, t , J=7.2) , 2.55 (4H,brs) , 2.50
(4H,brs), 2.30 (2.50,m), 1.69 (2H,m), 1.50 (2H,m)
Example 12
4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[5-(lH-tetrazol-5- yDpentyl] piper idine:
Colorless powder
MS(m/z): 412(M+H), (SIMS)
IR(nujol): cm-1: 1650, 1550, 1300, 1250, 950, 800, 760
NMR(DMS0-d6) δppm: 7.51 (4H,m), 7.43 (2H,m), 7.33
(2H,d,J=8.3) , 7.10 (2H,s), 2.94 (2H,t,J=7.2) ,2.75
(2H,t.J=7.2) , 2.40 (4H,t,J=6.9) , 2.16 (4H,m), 1.80 (2H,m),
1.59 (2H,m). 1.44 (2H,m)
Example 13
4-Xanthen-9-ylidene-l-[3-(lH-tetrazol-5- yDpropyl)piperidine:
m.p. ≥ 250 °C (from ethyl acetate)
MS(m/z): 374(M+H), (SIMS)
IR(nujol): cm"1: 2450, 1590, 1550, 1250, 1200, 1150,
1100, 1060, 1050,
NMR(DMSO-dε) δppm: 7.2-7.7 (8H,m), 2.8-3.6 (12H,m),
2.25 (2H,quintet,J=7)
Example 14
4-Thioxanthen-9-ylidene-l-[3-(lH-tetrazol-5- yDpropyl]piperidine:
m.p ≥ 250 °C
MS(m/z): 390 (SIMS)
NMR(DMS0-d6) δppm: 7.2-7.7 (8H,m), 2.8-3.6 (12H,m),
2.26 (2H,quintet,J=7)
Example 15 l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-piperazine
Benzhydrylpiperazine (10.62 g,42 mmol), 4- broraobutyronitrile (6.23 g, 42 mmol) and potassium carbonate(11.6 g, 84 mmol) were suspended in acetonitrile (200ml) and stirred overnight at 60 βC. The reaction solution was cooled and, thereafter, the inorganic matter
was filtered off and the acetonitrile was concentrated under vacuum to yield an oil of 4-(4-benzhydrylpiperazin- l-yl)butyronitrile (13.4 g, 99%). MS (m/z) SI-MS,Pos: 319(M+H) IR (Neat), cm-1: 2250 (nitrile), 1490, 1445 Without further purification, 4-(4- benzhydrylpiperazin-l-yl)-butyronitrile was dissolved in DMF (150 ml) and ammonium chloride (6.74 g) and sodium azide (8.19 g) were added to the solution, followed by stirring at 90°C for 48 h. The reaction mixture was poured into water (300 ml) , extracted with ethyl acetate (200 ml) and the extract was removed.
Then, the aqueous layer was extracted twice with chloroform (200 ml). The chloroform layer was combined, dried with magnesium sulfate and concentrated under vacuum to reduce the volume of the solution to approximately 30 ml. Upon leaving the solution to stand, crystals precipitated and recovered by filtration to yield the titled compound
(5.5 g).
Decomposition point: 218 βC
MS (ra/z) SI-MS,Pos: 363 (M+H)
Elemental analysis for C2iH26N6
C H N Cal'd 69.58 7.23 23.19 found 69.70 7.32 23.10
IR(nujol) cm"1: 1405, 1310, 1192, 1087
1H-NMR(DMS0-d6) δppm: 50 βC , 1.84 (2H,m), 2.2-3.7 (lOH.m) .
2.85 (2H,m) , 4.27 (lH.s) , 5.60 (211 ,brs , H20) , 7.0-7.4 (lOH.m)
13C-NMR(DMS0-d6) δppm: 50°C, 156.07, 142.48, 128.16,
127.35. 126.54, 95.29, 74.83, 56.41, 52.42. 50.95. 23.80,
20.87
Exa ple 16 l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-[1,4]diazepan:
The titled compound was synthesized via an intermediate nitrile form as in Example 1. m.p. 172 - 175 °C (from ethyl acetate) MS (m/z) SI-MS : 377(M+H) Elemental analysis for C22H28N6 •1/2H20
C H N
Cal ' d 68 . 54 7 . 58 21 . 80 found 68.60 7.45 21.85
IR(nujol) cm-1: 1600, 1495, 1405, 1330, 1320 1H-NMR(DMS0-d6) δppm: 21.8°C, 1.81 (2H,m), 1.94 (2H,m), 2.4-2.7 (lOH.m), 3.13 (2H,m), 4.71 (lH,s), 7.0-7.4 (lOH.m)
Example 17 l-Benzhydryl-4-(lH-tetrazol-5-ylmethyl)piperazine:
m.p. 179 - 182°C (from ethyl acetate) MS(m/z) SI-MS,Pos : 335(M+H)
Elemental analysis for Cι9H22N6
C H N
Cal'd 68.24 6.63 25.13 found 68.10 6.54 25.10
IR(nujol) cm"1: 2450, 1600, 1490, 1410, 1340, 1190, 1080, 1040, 970, 750, 710
Example 18 l-Benzhydryl-4-[4-(lH-tetrazol-5-yl)butyl]-piperazine
m.p. 67 - 68°C
Elemental analysis for C22H28N6 c H N Cal'd 70.18 7.50 22.30 found 70.10 7.40 22.35 MS (m/z) SI-MS,Pos: 377(M+H)
IR(nujol) era"1: 1655, 1600, 1310. 1280, 1080, 970, 750, 710 1H-NMR(DMS0-d6) δppm: 1.56 (2H,m), 1.78 (2H,m) , 2.49 (2H,m), 2.60 (8H,s), 2.95 (2H,t,J=7.2) , 4.38 (lH.s), 7.28 (2H,t,J=7.0) , 7.39 (2H,t,J=7.2) , 7.52 (2H,d,J=7.6)
01350
-28 -
Example 19 l-[ (4-Chlorophenyl)phenylmethyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine dihydrochloride:
m.p. 198 - 203°C
MS(m/z) SI-MS, Pos: 397(M+H), 201, 166 Elemental analysis for C2ιH27 6Cl3
C H N
Cal ' d 53. 68 5 . 79 17 . 89 found 53.65 5.90 17.91
IR(nujol) cm"1: 1550, 1095, 1020, 760, 730
1H-NMR(DMS0-d6) tfppm: 2.13 (2H,m), 2.98 (2H,t,J=7.0) , 3.35
(4H,m), 3.63 (4H,m), 5.53 (lH.brs), 7.2-8.1 (9H,m)
Example 20
1-[Bis(4-fluorophenyl)methyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine:
m.p. 170 - 172°C
MS (m/z) SI-MS: 399(M+H),203
Elemental analysis for C2ιH24F2Nβ
C H N Cal'd 63.30 6.07 21.09 Found 63.25 6.10 21.21
IR(nujol) cm"1: 2100, 1600, 1500, 1400, 1300, 1225, 1090,
970, 870, 830, 725 iH-NMRtDMSO-de) δppm: 1.85 (2H,m), 2.50 (lOH.m), 2.86
(2H,t,J=7.3) ,4.36 (lH.s), 7.12 (4H,t,J=8.9) , 7.43
(4H,dd,J=8.2,5.9)
Example 21
4-Benzhydryloxy-l-[3-(lH-tetrazol-5-yl)propyl]piperidine:
The procedure of Example 20 was repeated to synthesize 4-(4-benzhydryloxypiperidin-l-yl)butyronitrile (2g, 5.3 mmol). This compound, as well as tributyltin azide (3.35 g, 10.6 mmol) were stirred in dimethoxyethane (DME) at 90 βC for 48 h. Water was added to the reaction solution, followed by the addition of ethyl acetate (20 ml) and hexane (100 ml). The precipitating crystals were recovered by filtration and recrystallized from chloroform-ether to produce the titled compound (1.8 g) in a yield of 80%. m.p. 216 - 217βC
MS (m/z) SI-MS. Pos: 378(M+H) ,167,133 Elemental analysis for C22H27Ns0
C H N
Cal'd 70.00 7.21 18.55
Found 70.31 7.30 18.70
IR(nujol) cm-1 1500, 1400, 1300, 1260, 1220, 1110, 1060, 960, 745, 705
iH-NMR (DMSO-de) δppm: 1.47 (2H,m), 1.96 (4H,m), 2.49 (2H,t,J=9.5) , 2.68 (2H,t,J=6.7) , 2.93 (4H,m), 5.73 (lH,s), 7.31 (2H,t,J=6.1Hz) , 7.43 (8H,m)
Example 22
4-[ (4-Chlorophenyl)phenylmethoxy]-l-[3-(lH-tetrazol-5- yDpropyl]piperidine:
The procedure of Example 1 was repeated to synthesize 4-{4-[ (4-chlorophenyl)phenylmethoxy]piperidin- l-yl}butyronitrile (1.7 g, 4.6 mmol). This compound, as well as tributyltin azide (2.87 g, 9.2 mmol) were stirred in dimethoxyethane (DME) at 90 βC for 48 h. Acetonitrile (10 ml) was added to the reaction solution, which was further stirred for 6 h at 90 °C. Water was added to the reaction solution and the precipitating crystals were recovered by filtration. Upon recrystallization from chloroform-ether, the titled compound was obtained (1.3 g) in a yield of 69%. m.p. 210 - 213°C
MS (m/z) SI-MS: 412(M+H), 201, 165 Elemental analysis for C22H26C1N50
C H N
Cal'd 64.15 6.36 17.00
Found 64.13 6.50 17.20
IR(nujol) cm"1: 1495, 1400, 1300, 1090, 1055, 750, 710 lH-NMR(DMSO-de) δppm: 1.75 (2H,m), 1.99 (4H,m), 2.61 (2H,m), 2.76 (2H,t,J=6.9) , 2.93 (2H,t,J=7.3) , 3.01 (2H,m), 5.73 (lH.s) , 7.44 (9H.m)
Exa p l e 23
4[Bis(4-fluorophenyl)methoxy]-l-[3-(lH-tetrazol-5- yDpropyl]-piperidine:
Colorless powder
MS (m/z) SI-MS,Pos: 414(M+H), 203 Elemental analysis for C22H2sN502F2
C H N
Cal'd 63.91 6.09 16.94
Found 63.81 6.20 16.90
Hydrochloride
IR(nujol) cm"1: 1500, 1400, 1260, 1120, 970, 830, 725 1H-NMR(DMSO-d6) δppm: 1.95 (2H,m), 2.16 (4H.m), 2.92 (8H,m), 3.52 (lH.m), 5.70 (lH.s), 7.15 (4H,m), 7.40 (4H,m)
Example 24
4-[ (4-chlorophenyl)phenylmethoxy]-1-[4-(lH-tetrazol-5- yl)butyl]piperidine:
Colorless powder
FAB-MS (m/z) 425(M+H), 278, 202, 187
IR(nujol) cm"1: 1500, 1400, 1260, 1120, 970, 830, 725
1H-NMR(DMS0-d6) δppm: 7.2-7.4 (9H.m), 5.62 (lH.s), 3.38
(lH.m), 2.84 (2H,t,J=6), 2.73 (2H,m), 2.37 (2H,t,J=6), 2.16
(2H,m), 1.4-2.0 (8H,m)
Example 25
4-[(4-Chlorophenyl)phenylmethylene]-l-[3-(lH-tetrazol-5- yl)propyl]piperidine:
Colorless powder
MS (m/z) SI-MS,Pos: 393(M+H), 360, 296. 140 Elemental analysis for C22H23N5 •1.5H20
C H N
Cal ' d 62 . 93 6 . 23 16 . 68
Found 63.15 5.90 17.09
IR (KBr) cm"1: 3435. 2565, 1487, 1089. 1031, 964, 825, 763, 703, 509 H-NMR (CDC13) δppm: 7.32 (5H,m), 7.18 (4H,m), 3.20 (4H,m), 3.09 (4H,m), 2.87 (4H,m), 2.23 (2H,t,J=6)
Example 26
4-(Dibenzo[a,d]cycloheptan-5-yl)-l-[3-(lH-tetrazol-5- yl)propyl]piperazine dihydrochloride:
White amorphous
MS (m/z) SI-MS, Pos: 389(M+H), 194. 178, 114 Elemental analysis for C24H30N62HC1 -H20
C H N
Cal ' d 57 . 62 6 . 30 17 . 53
Found 57.73 6.78 17.43
IR (KBr) cm"1: 2997, 2725, 2584, 1635, 1560, 1442, 1419,
1076, 906, 630 iH-NMR (CDC13) δppm: 7.35 (8H,m), 5.21 (lH.brs), 3.90
(2H.m). 3.37 (2H,brt), 3.27 (2H,t,J=6), 3.08 (4H,m), 2.31
(2H,m)
Example 27
4-(Dibenzo[a,d]cycloheptan-5-yl)-l-[4-(lH-tetrazol-5- yl)butyl]piperazine dihydrochloride :
White amorphous
MS (m/z) SI-MS. Pos 403(M+H), 193
Elemental analysis for C24H30N6 •2HC1•0.5H20
C H N
Cal'd 59.50 6.44 17.35
Found 59.41 7.03 16.91
IR (KBr) cm-1: 2960, 1564, 1446, 1396, 1058, 773. 744 iH-NMR(CDCls) δppra: 7.38 (4H.m) . 7.27 (4H,m) , 5.21 (IH.brs). 3.91 (2H,m) , 3.39 (2H,m), 3.22 (6H,m), 3.01 (4H,m), 1.87(4H,m)
Example 28
4-(6H-Dibenzo[b,e]-oxepin-ll-yl)-l-[3-(lH-tetrazol-5- yl)propyl]piperazine:
White amorphous
MS (m/z) FAB-MS, Pos: 391(M+H), 195
IR(KBr) cm"1: 3389, 2869, 1606, 1574, 1478, 1456, 1255,
1228, 1109, 1004, 761, 725, 638
1H-NMR(CDC13) δppm: 7.30 (4H,m), 7.15 (2H,t,J=7.5) , 6.82
(2H,t,J=7.5) , 6.72 (IH,d,J=ll.5) , 4.73 (IH,d,J=ll.9) , 4.03
(lH.s), 3.09 (2H,m), 2.73 (8H,m),
1.9-2.1 (2H,m)
Exa ple 29
4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[3-(lH-tetrazol-5- yDpropyl] piper idine:
White amorphous
MS (m/z) FAB-MS, Pos: 387 (M+H) . 191
IR(KBr) cm"1 : 3392. 1654, 1436. 1402. 1276, 1103. 973. 796.
763, 730, 628, 493 1H-NMR(CDC13) δppm: 7.37 (8H,m), 6.94 (2H,s), 4.48 (lH.s), 3.18 (2H,t-like) 2.73 (2H,t-like), 2.69 (4H,m), 2.29 (4H,m). 1.95 (2H,m)
Example 30
4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[4-(lH-tetrazol-5- yl)butyl]piperidine :
White amorphous
MS (m/z) FAB-MS, Pos: 401(M+H), 191
IR(KBr) cm"1 : 3045, 2871, 1635, 1436, 1402, 1247, 1103,
997. 798, 763. 730, 464 iH-NMRtCDCla) δppm: 7.31 (8H,m) , 6.94 (2H, S) , 4.40 (lH.s).
2.92 (2H,t,J=6.0) , 2.64 (6H,m), 2.28 (4H, t ,J=4.6) , 1.78
(2H,m), 1.63 (2H,m)
Exa ple 31
4-(6H-Dibenzo[b,e]oxepin-ll-yl)-l-[4-(lH-tetrazol-5- yl)butyl]-piperazine:
White amorphous
MS (m/z) FAB-MS,Pos: 405(M+H). 195
IR(KBr) cm"1: 3485, 1487, 1446, 1255, 1228, 1109, 1004, 765 iH-NMR CDCls) δppm: 7.29 (6H,m), 6.82 (2H,m), 6.69
(lH,d,J=11.5) , 4.72 (IH,d,J=ll.5) , 4.00 (lH.s), 3.00
(2H,t,J=5.6) , 2.5-2.9 (lOH.m), 1,87 (2H.m) , 1.71 (2H.m)
Example 32
4-[ (4-Chlorophenyl)phenylmethylene]-1-[4-(lH-tetrazol-5- yl)butyl]piperidine:
White amorphous
MS (m/z) FAB-MS,Pos: 408(M+H), 296
IR(KBr) cm"1: 3438, 3099, 2763, 2650, 1487, 1442, 1398,
1087, 1014, 829, 763, 703 lH-NMR(CDCl3) δppm: 7.26 (5H,m), 7.04 (4H,m), 3.00 (4H,t- like), 2.87 (2H,t-like), 2.70 (4H,t-like), 1.83 (4H.m)
Example 33
4-[ (4-Chlorophenyl)phenylmethylene]-l-[3-(lH-tetrazol-5- yl)propyl)piperidine:
White amorphous
MS (m/z) FAB-MS. Pos: 393(M+H) , 296
IR(KBr) cm"1: 3436, 2565, 1487, 1089, 1031, 825, 763, 703
1H-NMR(CDC13) δppm: 7.32 (5H,m), 7.08 (4H,m), 3.15 (6H,m),
2.87 (2H,t-like), 2.30 (2H,m)
Example 34
4-[Bis(4-methoxyphenyl)methylene]-1-(ethoxycarbonyl)- piperidine:
A zinc powder (40.5 g, 0.62 mmol) was suspended in dry THF (500 ml) and titanium tetrachloride (34 ml, 0.30 mol) was added dropwlse to the suspension at -10βC or below. The mixture was dried for 0.5 h and thereafter heated at 80 °C for 1 h. The reaction solution was cooled again to 0βC and both 4,4'-dimethoxy-benzophenone (25 g, 0.103 mol) and 1-ethoxycarbonylpiperidone (18 g, 0.103 mol) as dissolved in THF (100 ml) were added. The reaction mixture was transferred to an oil bath, where it was heated under reflux at 80 βC for 2 h. The reaction solution was cooled and poured into an aqueous solution of potassium carbonate. The THF layer was recovered and subjected to extraction with ethylacetate. The extracts were combined, dried and concentrated. The concentrate was subjected to silica gel chromatography and eluted with ethyl acetate- hexane (2:8) to yield the end product (34 g, 94%).
Oil
IR(nujol) cm"1: 1735, 1605, 1578, 1490, 1390, 1130
XH-NMR(DMSO-de) δppm: 7.01 (4H,d,J=9), 6.82 (4H,d,J=9),
4.15 (2H,q,J=7), 3.78 (6H,s), 3.49 (4H,m), 2.35 (4H,m), 1.25
(3H,t,J=7)
Exa ple 35
4-[Bis(4-methoxyphenyl)methylene]piperidine:
4-[Bis(4-methoxyphenyl)methylene]-l- (ethoxycarbonyl)piperidine (35 g) was dissolved in ethanol (300 ml) and potassium hydroxide (120 g) was added to the solution, which was then stirred over-night. Ethanol was concentrated, mixed with water (500 ml), subjected to extraction with chloroform (200 ml) , dried and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to yield the end compound (20 g) .
*H-NMR (CDC13) δppm: 7.01 (4H,d,J=9), 6.82 (4H,d,J=9), 3.78 (6H,s), 2.90 (4H,m) , 2.32 (4H,m)
Claims
CLAIMS 1. A tetrazole derivative of the general formula (1):
(where A represents -CH=CH-, -CH2-CH2-, -CH20-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together with Z or represents a hydroxyl group, or (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively; p represents an integer of 2 or 3; and n represents an integer of 1 - 6) or a pharmacologically acceptable salt thereof. 2. An antihistamine, an antiallergic agent or an asthma treating agent that contain as an active ingredient a tetrazole derivative of the general formula (1):
(where A represents -CH=CH-, -CH2-CH2-, -CH20-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents
two hydrogen atoms each bonded to the adjacent aromatic ring, V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together with Z or represents a hydroxyl group, or (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively; p represents an integer of 2 or 3; and n represents and integer of 1 - 6) or a pharmacologically acceptable salt thereof.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15874593 | 1993-06-29 | ||
| JP15874193 | 1993-06-29 | ||
| JP5-158745 | 1993-06-29 | ||
| JP5-158741 | 1993-06-29 | ||
| JP6-138756 | 1994-06-21 | ||
| JP13875694A JP3338913B2 (en) | 1993-06-29 | 1994-06-21 | Tetrazole derivative |
| PCT/JP1994/001010 WO1995001350A1 (en) | 1993-06-29 | 1994-06-23 | Tetrazole derivatives having antihistaminic and antiallergic activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6983094A true AU6983094A (en) | 1995-01-24 |
| AU673754B2 AU673754B2 (en) | 1996-11-21 |
Family
ID=27317735
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU69830/94A Expired - Fee Related AU673754B2 (en) | 1993-06-29 | 1994-06-23 | Tetrazole derivatives having antihistaminic and antiallergic activity |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0706522A1 (en) |
| JP (1) | JP3338913B2 (en) |
| KR (1) | KR960703405A (en) |
| AU (1) | AU673754B2 (en) |
| CA (1) | CA2165792A1 (en) |
| IL (1) | IL110144A0 (en) |
| TW (1) | TW281677B (en) |
| WO (1) | WO1995001350A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3779349B2 (en) * | 1995-04-24 | 2006-05-24 | 興和株式会社 | Piperidine derivatives |
| WO1998004554A1 (en) * | 1996-07-29 | 1998-02-05 | Banyu Pharmaceutical Co., Ltd. | Chemokine receptor antagonists |
| ES2172436B1 (en) * | 2000-10-31 | 2004-01-16 | Almirall Prodesfarma Sa | INDOLILPIPERIDINE DERIVATIVES AS ANTIHISTAMINIC AND ANTIALERGIC AGENTS. |
| US7355042B2 (en) * | 2001-10-16 | 2008-04-08 | Hypnion, Inc. | Treatment of CNS disorders using CNS target modulators |
| US7189757B2 (en) | 2001-10-16 | 2007-03-13 | Hypnion, Inc. | Treatment of sleep disorders using CNS target modulators |
| US20050009730A1 (en) | 2001-10-16 | 2005-01-13 | Dale Edgar | Treatment of cns disorders using cns target modulators |
| ES2201907B1 (en) | 2002-05-29 | 2005-06-01 | Almirall Prodesfarma, S.A. | NEW DERIVATIVES OF INDOLILPIPERIDINE AS POWERFUL ANTIHISTAMINIC AND ANTIALERGIC AGENTS. |
| KR20050085673A (en) * | 2002-12-18 | 2005-08-29 | 에프엠씨 코포레이션 | N-(substituted arylmethyl)-4-(disubstituted methyl)piperidines and piperazines |
| US7482460B2 (en) | 2003-12-10 | 2009-01-27 | Hypnion, Inc. | Doxepin analogs and methods of use thereof |
| US7411069B2 (en) | 2003-12-10 | 2008-08-12 | Hypnion, Inc. | Doxepin analogs and methods of use thereof |
| US7326721B2 (en) | 2003-12-10 | 2008-02-05 | Hypnion, Inc. | Doxepin analogs and methods of use thereof |
| US7524864B2 (en) | 2004-04-23 | 2009-04-28 | Hypnion, Inc. | Methods of treating sleep disorders |
| CN101282954A (en) * | 2005-08-08 | 2008-10-08 | 阿斯利康(瑞典)有限公司 | Therapeutic agents |
| TWI457341B (en) * | 2008-08-01 | 2014-10-21 | Nippon Zoki Pharmaceutical Co | Aminopropyl derivative |
| EP3645257A1 (en) * | 2017-06-30 | 2020-05-06 | Nikon Corporation | A method of producing an optical device and a corresponding system |
| US11883410B2 (en) | 2018-04-19 | 2024-01-30 | National University Corporation Tokyo University Of Agriculture And Technolgy | Preventative and therapeutic agents for sarcopenia |
| CN113880808B (en) * | 2020-07-03 | 2024-12-31 | 合肥医工医药股份有限公司 | A triazole compound, preparation method and medical use thereof |
| US12220411B1 (en) | 2023-07-25 | 2025-02-11 | The Eye Hospital Of Wenzhou Medical University | Application of PTGDS inhibitor in preparation of drug for treating cataracts |
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| FI75816C (en) * | 1981-02-06 | 1988-08-08 | Ucb Sa | Process for the preparation of therapeutically active 2- [4- (diphenylmethyl) -1-piperazinyl] -acetic acid or its amide |
| JPH03246287A (en) * | 1990-02-22 | 1991-11-01 | Hokuriku Seiyaku Co Ltd | Piperazine derivative |
| FR2665160A1 (en) * | 1990-07-26 | 1992-01-31 | Esteve Labor Dr | NOVEL DERIVATIVES OF 1-DIPHENYLMETHYLPIPERAZINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS. |
| FR2665161B1 (en) * | 1990-07-26 | 1992-11-27 | Esteve Labor Dr | NOVEL BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS. |
-
1994
- 1994-06-21 JP JP13875694A patent/JP3338913B2/en not_active Expired - Fee Related
- 1994-06-23 EP EP94918560A patent/EP0706522A1/en not_active Withdrawn
- 1994-06-23 KR KR1019950705952A patent/KR960703405A/en not_active Application Discontinuation
- 1994-06-23 AU AU69830/94A patent/AU673754B2/en not_active Expired - Fee Related
- 1994-06-23 CA CA002165792A patent/CA2165792A1/en not_active Abandoned
- 1994-06-23 WO PCT/JP1994/001010 patent/WO1995001350A1/en not_active Application Discontinuation
- 1994-06-27 TW TW083105824A patent/TW281677B/zh active
- 1994-06-28 IL IL11014494A patent/IL110144A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR960703405A (en) | 1996-08-17 |
| EP0706522A1 (en) | 1996-04-17 |
| TW281677B (en) | 1996-07-21 |
| IL110144A0 (en) | 1994-10-07 |
| CA2165792A1 (en) | 1995-01-12 |
| JP3338913B2 (en) | 2002-10-28 |
| WO1995001350A1 (en) | 1995-01-12 |
| JPH0770112A (en) | 1995-03-14 |
| AU673754B2 (en) | 1996-11-21 |
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