NO142174B - Analogifremgangsmaate til fremstilling av terapeutisk virksomme 1,1-diaryl-1-oksadiazol-alkylaminer - Google Patents
Analogifremgangsmaate til fremstilling av terapeutisk virksomme 1,1-diaryl-1-oksadiazol-alkylaminer Download PDFInfo
- Publication number
- NO142174B NO142174B NO751104A NO751104A NO142174B NO 142174 B NO142174 B NO 142174B NO 751104 A NO751104 A NO 751104A NO 751104 A NO751104 A NO 751104A NO 142174 B NO142174 B NO 142174B
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- Norway
- Prior art keywords
- compound
- hydroxy
- acid
- diphenyl
- parts
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 15
- 150000003973 alkyl amines Chemical class 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 150000002440 hydroxy compounds Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims 1
- 230000000996 additive effect Effects 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical class C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000003610 charcoal Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- -1 5-(1,1-diphenyl-3-(4-hydroxy-4-phenylpiperidino)propyl)-2-methyl-1,3,4-oxadiazole Chemical compound 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000001142 anti-diarrhea Effects 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
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- CYIGQSPICYMIRV-UHFFFAOYSA-N 1-[3,3-diphenyl-3-(2h-tetrazol-5-yl)propyl]-4-phenylpiperidin-4-ol Chemical compound C1CC(O)(C=2C=CC=CC=2)CCN1CCC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1N=NNN=1 CYIGQSPICYMIRV-UHFFFAOYSA-N 0.000 description 2
- KQKFQBTWXOGINC-UHFFFAOYSA-N 4-phenylpiperidin-4-ol Chemical compound C=1C=CC=CC=1C1(O)CCNCC1 KQKFQBTWXOGINC-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FMPVGXVHNVGVQJ-UHFFFAOYSA-N [1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)-3,3-diphenylpropyl]-4-phenylpiperidin-4-yl] acetate Chemical compound C1(=CC=CC=C1)C(CCN1CCC(CC1)(C1=CC=CC=C1)OC(C)=O)(C1=CC=CC=C1)C1=NN=C(O1)C FMPVGXVHNVGVQJ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- TUNBQLBVMAHJLA-UHFFFAOYSA-N 1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)-3,3-diphenylpropyl]-4-phenylpiperidine-4-carboxylic acid Chemical compound O1C(C)=NN=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)CCN1CCC(C=2C=CC=CC=2)(C(O)=O)CC1 TUNBQLBVMAHJLA-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- LZAYOZUFUAMFLD-UHFFFAOYSA-N 4-(4-chlorophenyl)-4-hydroxypiperidine Chemical compound C=1C=C(Cl)C=CC=1C1(O)CCNCC1 LZAYOZUFUAMFLD-UHFFFAOYSA-N 0.000 description 1
- IGYSFJHVFHNOEI-UHFFFAOYSA-N 4-bromo-2,2-diphenylbutanenitrile Chemical compound C=1C=CC=CC=1C(C#N)(CCBr)C1=CC=CC=C1 IGYSFJHVFHNOEI-UHFFFAOYSA-N 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- HYPPXZBJBPSRLK-UHFFFAOYSA-N diphenoxylate Chemical compound C1CC(C(=O)OCC)(C=2C=CC=CC=2)CCN1CCC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 HYPPXZBJBPSRLK-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- WPHGSKGZRAQSGP-UHFFFAOYSA-N methylenecyclohexane Natural products C1CCCC2CC21 WPHGSKGZRAQSGP-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/06—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing isoquinuclidine ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Hydrogenated Pyridines (AREA)
Description
Foreliggende oppfinnelse angår fremstilling av terapeutisk virksomme 1,1-diaryl-l-oksadiazol-alkylaminer med den generelle formel:
samt syreaddisjonssalter derav, hvor X er hydrogen eller klor, og Z er hydroksy, alkanoyloksy hvor alkanoylgruppen inneholder 1-4 karbonatomer, karboksy og alkoksykarbonyl hvor alkoksy-gruppen inneholder 1-4 karbonatomer.
De organiske baser med formel I danner ikke-toksiske syreaddisjonssalter med en rekke organiske og uorganiske syrer. Slike salter kan dannes med syrer som svovelsyre, fosforsyre, saltsyre, hydrobromsyre, hydrojodsyre, svovelsyre, sitronsyre, melkesyre, maleinsyre, eplesyre, ravsyre, tartarsyre, kanelsyre, eddiksyre, benzosyre, klukonsyre, askorbinsyre og nær beslektede syrer.
Forbindelsene med formel I fremstilles ifølge foreliggende oppfinnelse ved at man omsetter en forbindelse med den generelle formel:
hvor X og Z har den ovenfor angitte betydning, med en forbindelse med formelen: eller
og når Z er alkanaoyloksy, kan man etter en slik fremgangsmåte foreta hydrolyse for oppnåelse av en tilsvarende hydroksyforbindelse, eller når Z er karbetoksy, kan denne hydrolyseres til karboksy, hvoretter, om ønsket, en således erholdt forbindelse omdannes til et farmakologisk akseptabelt syreaddisjonssalt derav.
Ved den ovenfor angitte omsetning anvendes et egnet opp-løsningsmiddel slik som pyridin eller ethvert inert oppløsnings-middel som toluen, benzen, metylenklorid eller cykloheksan i nærvær av et syreabsorberende middel så som trietylamin, piperi-din eller kaliumkarbonat, hvorved man får fremstilt oksadiazol-forbindelsen med formel I. Når Z er en lavere alkanoyloksygruppe, kan ovennevnte fremgangsmåte følges av en hydrolyse hvorved man får den tilsvarende hydroksyforbindelse. Denne fremgangsmåte brukes for fremstilling av hydroksyforbindelsene fordi man under reaksjonen med tetrazolen og nevnte acyleringsmiddel vil få omdannet eventuelle frie hydroksygrupper til de tilsvarende estere.
Utgangsforbindelsen med formel II kan fremstilles ved å omsette en forbindelse med følgende generelle formel:
hvor X og Z ersom definert ovenfor, med et azidion ved metoder ifølge Gi Moersch og D. Morrow, "J. Med.Chem.", 10, 149 (1967) . Forbindelser med formel I har utpregede anti-diareegenskaper og disse kan spesielt illustreres ved den aktivitet som utvises av forbindelsen 5-(1,i-difenyl-3-(4-hydroksy-4-fenylpiperidino)propyl)-2-metyl-l,3,4-oksadiazol.
At forbindelsene har anti-diareegenskaper kan påvises
ved deres evne til å hemme tarmbevegelighet slik det er angitt i den følgende prøve.
Trekullmåltidsprøve
Den fremgangsmåte som ble brukt i denne undersøkelse bygger på den teknikk, som tidligere er beskrevet (Macht og Barba-Gose, 1931 og Janssen og Jageneau, 1957). Charles River hanmus (20-25 g, n=6) på forhånd fastet i 24 timer, ble forbe- j handlet med prøveforbindelsene som ble tilført oralt som en oppløsning i vann eller suspendert i 0,5% metylcellulose. Man : anvendte et konstant volum på 10 ml/kg kroppsvekt. Tretti minutter etter tilførselen av prøveforbindelsene ble dyrene gitt en enkel oral dose av trekull (0,s ml pr. mus av en 10% trekull-suspensjon suspendert i 1,0% metylcellulose). Tre og.en halv time etter trekulltilførselen ble dyrene obdusert og Coecum undersøkt for nærvær eller fravær av trekull på en alle eller ingenbasis. Den midlere effektive dose (ED^q) ble beregnet for hver forbindelse ved å bruke Berksons logistiske metode (1953).
I tillegg til at forbindelser med formel I har antidiare-aktivitet, har de også sterk smertestillende aktivitet. Denne egenskap ble prøvet ved hjelp av den såkalte haleklemmeprøve.
Haleklemmeprøve
En spesiell klemme ble påsatt basis av halen på musen (voksne hannmus som veide fra 18-25 gram), og den tid det tok før dyret snudde seg rundt for å bite ble målt. Hver mus' føl-somhet ble bestemt .en halv time før man tilførte prøveforbin-delsen. Bare de mus som prøvde å bite i klemmen ble inkludert i eksperimentet. Prøveforbindelsen ble så tilført intraperi-sonalt, og reaksjonen overfor klemmen ble bestemt etter 30, 60,
90 og 120 minutter etter behandlingen. En reaksjon ble ansett
å være positiv hvis dyret brukte mer enn to ganger den tid det brukte før forbindelsen ble tilført, til. å prøve å bite klemmen på et hvert av de nevnte tidsintervaller. En prøveforbindelse
ble ansett å være aktiv når 50% eller mer av dyrene viste en positiv reaksjon.
Følgende eksempler illustrerer oppfinnelsen. I eksemp-lene er de relative mengder pr. vektdeler hvis intet annet er
angitt.
Eksempel 1
En blanding av 15 deler 2,2-difenyl-4-brombutyronitril, 8.9 deler 4-hydroksy-4-fenyl-piperidin og 400 volumdeler etylen-glykolmonometyleter ble oppvarmet til koking under tilbakeløp i 18 timer under en nitrogenatmosfære. Oppløsningen ble avkjølt, og volumet redusert med 50% ved 60°C under trykk. Den konsen-trerte blanding ble fortynnet med 1200 deler vann, gjort basisk med natriumhydroksyd og så ekstrahert med eter. Eteroppløsningen ble så ekstrahert med fortynnet saltsyre. Det gummiaktige faste stoff som dannet seg ble utskilt ved filtrering, vasket med vann og så med eter og deretter lufttørket. Det fremstilte produkt var 2,2-difenyl-4-(4-hydroksy-4-fenylpiperidin)butyronitril, smeltepunkt 221-223°C.
8,0 deler av dette nitril, 2,0 deler av natriumazid, 1,6 deler ammoniumklorid, 0,03 deler litiumklorid og 20 volumdeler dimetylformamid ble slått sammen og holdt på 125°C i 12 timer. Blandingen ble deretter avkjølt og det faste stoff ble frafiltrert fra dimetylformamidet. Det faste stoff ble så vasket med dimetylformamid og vann. Det tørkede faste stoff var 5-(1,l-difenyl-3-(4-hydroksy-4-fenylpiperidino)propyl)-lH-tetrazol.
3,16 deler av dette lH-tetrazol og 7,1 deler eddiksyre anhydrid ble kokt under tilbakeløp i 36 volumdeler pyridin i 1 time. Reaksjonsblandingen ble så avkjølt. Pyridinen ble fjernet ved fordamping under redusert trykk, hvorved man fikk et resi-dum. Dette ble så oppløst i eter, og eteroppløsningen ble så
vasket med natriumbikarbonatoppløsning. Etter vasking med basen, ble eteren fjernet og man fikk et råprodukt. Dette ble omkrystallisert fra pentan og man fikk 5-(1,l-difenyl-3-(4-acetoksy-4-fenylpiperidino)propyl)-2-metyl-l,3,4 oksadiazol, smeltepunkt 157,5-160°C.
Ved å bruke acetylklorid istedenfor eddiksyreanhydrid som angitt ovenfor, fikk man det samme produkt, nemlig 5-(l,l-difenyl-3-(4-acetoksy-4-fenylpiperidino)propyl)-2-metyl-l,3,4-oksadia-zol. Ved å bruke 4-hydroksy-4-(4-klorfenyl)piperidin' isteden : for 4-hydroksy-4-fenylpiperidin og bruker samme fremgangsmåte . som nevnt ovenfor, så fikk man fremstilt 5-(1,l-difenyl-3-(4-acetoksy-4-(4-klorofenyl)piperidinq)propyl)-2-metyl-l,3,4 oksadiazol, smeltepunkt 155-158°C. Eksempel 2
En del av ovennevnte 5-(1,1-difeny1^3-(4-acetoksy-4-: fenylpiperidino)propyl)-2-metyl-l,3,4-oksadiazol ble omdannet til 4-hydroksyforbindelsen ved hydrolyse i 55 deler metanol og 15 deler 20% natriumhydroksyd. Produktet ble isolert ved å for-dampe etanolen under redusert trykk, fortynne det hele med vann, tilsette natriumhydroksyd og så ekstrahere produktet over i metylenklorid. Etter fjerning av metylenkloridet ble produktet omkrystallisert fra eter, og man fikk 5-(1,l-difenyl-3-(4-hydroksy-4-fenylpiperidino)propyl)-2-metyl-l,3,4-oksadiazol, smeltepunkt 160-162°C.
Eksempel 3
Ved å bruke ekvivalente mengder og den fremgangsmåte
som er angitt i eksempel 1, ble 2,2-difenyl-4-(4-karbetoksy-4-fenylpiperidino)butyronitril omdannet til 5-(1,l-difenyl-3-(4-karbetoksy-4-fenylpiperidino)propyl)-lH-tetrazol. Ved å bruke samme fremgangsmåte som i eksempel 1 og bruke ekvivalente mengder, ble nevnte lH-tetrazol omdannet til 5-(1,l-difenyl-3-(4-karbetoksy-4-fenylpiperidino)propyl)-2-metyl-l,3,4-oksadiazol.
Hydrolyse av en del av denne ester i 50 deler metanol inneholdende 15 deler 20% vandig natriumhydroksyd og en etter-følgende isolasjon, gav 5-(1,l-difenyl-3-(4-karboksy-4-fenyl-piperidino) propyl)-2-metyl-l,3,4-oksadiazol.
Eksempel 4
Ved å bruke ekvivalente mengder og den fremgangsmåte
som er angitt i eksempel 1, ble 2,2-difenyl-4-(4-hydroksy-4-fenylpiperidinobutyronitril omdannet til 5-(1,l-difenyl-3-(4-hydroksy-4-fenylpiperidino)propyl)-lH-tetrazol. Ved å bruke pro-pionsyreanhydrid istedenfor eddiksyreanhydrid i fremgangsmåten fra eksempel 1, omdannet man lH-tetrazolforbindelsen til 5-(1,l-difenyl-3-(4-propionyloksy-4-fenylpiperidino)propyl)-2-ety1-1,3,4-oksadiazol.
Claims (1)
- Analogifremgangsmåte til fremstilling av terapeutisk aktive forbindelser med følgende formel:samt syreaddisjonssalter derav, hvor X er hydrogen eller klor, og Z er hydroksy, alkanoyloksy hvor alkanoylgruppen inneholder 1-4 karbonatomer, karboksy og alkoksykarbonyl hvor alkoksy-gruppen inneholder 1-4 karbonatomer, karakterisert ved at man omsetter en forbindelse med den generelle formel:hvor X og Z har den ovenfor angitte betydning, med en forbindelse med formelen:og når Z er alkanoyloksy, kan man etter en slik fremgangsmåte foreta hydrolyse for oppnåelse av en tilsvarende hydr<p>ksyfor-bindelse, eller når Z er karbetoksy, kan denne hydrolyseres til karboksy, og, om ønsket, omdannelse av en således erholdt forbindelse til et farmakologisk akseptabelt syreaddisjohssålt derav.
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US456755A US3917615A (en) | 1974-04-01 | 1974-04-01 | 1,1-Diaryl-1-oxadiazol-alkylamines |
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NO751103A NO142173C (no) | 1974-04-01 | 1975-04-01 | Analogifremgangsmaate til fremstilling av terapeutisk virksomme, 1,1-diaryl-1-oksadiazolalkylaminderivater |
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AR (2) | AR206425A1 (no) |
AT (2) | AT340916B (no) |
BE (2) | BE827324A (no) |
CA (2) | CA1067498A (no) |
CH (2) | CH614205A5 (no) |
CS (1) | CS194718B2 (no) |
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US4003904A (en) * | 1974-04-01 | 1977-01-18 | G. D. Searle & Co. | Anti-diarrheal oxadiazoles |
US3998832A (en) * | 1975-04-16 | 1976-12-21 | G. D. Searle & Co. | Anti-diarrheal compounds |
US4057549A (en) * | 1975-04-16 | 1977-11-08 | G. D. Searle & Co. | Triarylpropyl-azabicyclooctanes |
US4086227A (en) * | 1975-04-16 | 1978-04-25 | G. D. Searle & Co. | Novel anti-diarrheal 4-azatricyclo[4.3.1.13,8 ] undecane derivatives |
US4025524A (en) * | 1975-04-16 | 1977-05-24 | G. D. Searle & Co. | 2-{3-[4-Azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-5-methyl-1,3,4-oxadiazole and congeners |
US3996214A (en) * | 1976-02-23 | 1976-12-07 | G. D. Searle & Co. | 5-(1,1-Diphenyl-4-(cyclic amino) but-2-trans-en-1-yl)-2-alkyl-1,3,4-oxadiazoles and intermediates thereto |
US4013668A (en) * | 1976-03-10 | 1977-03-22 | G. D. Searle & Co. | 5-(1,1-diphenyl-3-(5- or 6-hydroxy-2-azabicyclo(2.2.2)oct-2-yl)propyl)-2-alkyl-1,3,4-oxadiazoles and related compounds |
US4012393A (en) * | 1976-03-22 | 1977-03-15 | G. D. Searle & Co. | 2-[5-(CYCLIC AMINO) ETHYL-10,11-DIHYDRO-5H-dibenzo[a,d]-cyclohepten-5- yl]-5 |
US4028364A (en) * | 1976-07-06 | 1977-06-07 | G. D. Searle & Co. | 2-Azabicyclo[2.2.2.]octan-2-yl-diphenyl-alkanones and related compounds |
US4053477A (en) * | 1976-09-20 | 1977-10-11 | G. D. Searle & Co. | 5-(1,1-diphenyl-3-(4-phenylpiperidino)propyl)-2-methyl-1,3,4-oxadiazole and related compounds |
US4194045A (en) * | 1977-12-27 | 1980-03-18 | G. D. Searle & Co. | 1-(3,3-Diaryl-3-oxadiazolalkyl)-4-phenyl-4-piperidinomethanols and related compounds |
US4203990A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal 2-substituted quinuclidines |
US4203989A (en) * | 1979-04-30 | 1980-05-20 | G. D. Searle & Co. | Anti-diarrheal diaryl-(1-azabicyclo(2.2.2)octan-2-yl)-alkanols and related compounds |
US4596801A (en) | 1983-03-24 | 1986-06-24 | Chugai Seiyaku Kabushiki Kaisha | 4H-3,1-benzoxazine derivatives, process for producing the same and agricultural or horticultural fungicide containing the same |
JPS61194917A (ja) * | 1985-02-23 | 1986-08-29 | Matsushita Electric Works Ltd | 遅れスイツチ |
JPS61195022A (ja) * | 1985-02-25 | 1986-08-29 | Matsushita Electric Works Ltd | 遅れスイツチ |
GB8830226D0 (en) * | 1988-12-23 | 1989-02-22 | Beecham Group Plc | Novel compounds |
DK40890D0 (da) * | 1990-02-16 | 1990-02-16 | Ferrosan As | Substituerede urinstofforbindelser, deres fremstilling og anvendelse |
US5889038A (en) * | 1996-03-20 | 1999-03-30 | Children's Hospital | Methods and products for treating diarrhea and scours: use of clotrimazole and related aromatic compounds |
BR112013030031A2 (pt) | 2011-05-27 | 2016-09-13 | Reliance Ind Ltd | hidrólise e esterificação com catalisadores ácidos |
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US3141019A (en) * | 1964-07-14 | Chaohj | ||
US3299044A (en) * | 1964-05-13 | 1967-01-17 | Searle & Co | Complex n-substituted azabicycloalkanes |
FR1469022A (fr) * | 1965-12-14 | 1967-02-10 | Chimie Et Synthese De Picardie | Nouveaux dérivés oxadiazoliques et leur procédé de préparation |
GB1174411A (en) * | 1966-03-02 | 1969-12-17 | Aspro Nicholas Ltd | Novel Benzothiophen Compounds, Compositions containing them and processes for their manufacture |
GB1231829A (no) * | 1968-09-19 | 1971-05-12 | ||
US3720685A (en) * | 1970-07-15 | 1973-03-13 | Squibb & Sons Inc | 3-amino-5-benzyl-1,2,4-oxadiazoles |
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- 1974-04-01 US US456755A patent/US3917615A/en not_active Expired - Lifetime
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1975
- 1975-01-01 AR AR258169A patent/AR206425A1/es active
- 1975-02-26 ZA ZA00751193A patent/ZA751193B/xx unknown
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- 1975-03-28 FR FR7509995A patent/FR2265367B1/fr not_active Expired
- 1975-03-28 FR FR7509996A patent/FR2265376B1/fr not_active Expired
- 1975-03-28 BE BE154890A patent/BE827324A/xx not_active IP Right Cessation
- 1975-03-28 IL IL46959A patent/IL46959A/xx unknown
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- 1975-03-28 HU HUSE1776A patent/HU170747B/hu unknown
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- 1975-03-31 YU YU00816/75A patent/YU39200B/xx unknown
- 1975-03-31 ES ES436160A patent/ES436160A1/es not_active Expired
- 1975-03-31 OA OA55456A patent/OA04914A/xx unknown
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- 1975-04-01 SE SE7503688A patent/SE420491B/xx not_active IP Right Cessation
- 1975-04-01 DK DK137375A patent/DK137375A/da not_active Application Discontinuation
- 1975-04-01 NL NL7503849A patent/NL7503849A/xx not_active Application Discontinuation
- 1975-04-01 PL PL1975179255A patent/PL99553B1/pl unknown
- 1975-04-01 AT AT245175A patent/AT340916B/de not_active IP Right Cessation
- 1975-04-01 DK DK137275A patent/DK137275A/da not_active IP Right Cessation
- 1975-04-01 FI FI750965A patent/FI63572C/fi not_active IP Right Cessation
- 1975-04-01 SE SE7503689A patent/SE420492B/xx unknown
- 1975-04-01 CH CH410975A patent/CH614205A5/xx not_active IP Right Cessation
- 1975-04-01 CH CH410875A patent/CH613964A5/xx not_active IP Right Cessation
- 1975-04-01 GB GB1318675A patent/GB1456943A/en not_active Expired
- 1975-04-01 DE DE19752514229 patent/DE2514229A1/de not_active Ceased
- 1975-04-01 NO NO751104A patent/NO142174C/no unknown
- 1975-04-01 NL NL7503856A patent/NL7503856A/xx not_active Application Discontinuation
- 1975-04-01 DE DE19752514183 patent/DE2514183A1/de not_active Withdrawn
- 1975-04-01 CA CA223,485A patent/CA1067498A/en not_active Expired
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1976
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