NO853694L - VINYLTETRAZOLYLPHENYL DERIVATIVES, PREPARATION AND USE THEREOF. - Google Patents
VINYLTETRAZOLYLPHENYL DERIVATIVES, PREPARATION AND USE THEREOF.Info
- Publication number
- NO853694L NO853694L NO853694A NO853694A NO853694L NO 853694 L NO853694 L NO 853694L NO 853694 A NO853694 A NO 853694A NO 853694 A NO853694 A NO 853694A NO 853694 L NO853694 L NO 853694L
- Authority
- NO
- Norway
- Prior art keywords
- tetrazol
- phenyl
- tetramethyl
- propene
- indenyl
- Prior art date
Links
- -1 VINYLTETRAZOLYLPHENYL Chemical class 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 150000001540 azides Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 239000005977 Ethylene Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 208000002874 Acne Vulgaris Diseases 0.000 description 4
- 206010000496 acne Diseases 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000009121 systemic therapy Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- XUDBVJCTLZTSDC-UHFFFAOYSA-N 2-ethenylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C=C XUDBVJCTLZTSDC-UHFFFAOYSA-N 0.000 description 2
- VADHCDOLBCEYDU-JQIJEIRASA-N 5-[4-[(e)-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-enyl]phenyl]-2h-tetrazole Chemical compound C=1C=C(C(CCC2(C)C)(C)C)C2=CC=1C(/C)=C/C(C=C1)=CC=C1C1=NN=NN1 VADHCDOLBCEYDU-JQIJEIRASA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N ethyl ethylene Natural products CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229910001502 inorganic halide Inorganic materials 0.000 description 2
- 230000003780 keratinization Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000009826 neoplastic cell growth Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 2
- 150000003536 tetrazoles Chemical class 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- HFSYUFOZUAJWDE-UHFFFAOYSA-N (n,n-dimethylcarbamimidoyl)-methyl-methylideneazanium;azide Chemical compound [N-]=[N+]=[N-].CN(C)C(=N)[N+](C)=C HFSYUFOZUAJWDE-UHFFFAOYSA-N 0.000 description 1
- ITKWEXDHDYDKPX-UHFFFAOYSA-N 1,1,4,4-tetramethyl-6-[1-[4-(2H-tetrazol-5-yl)phenyl]prop-1-en-2-yl]naphthalene-2,3-dione Chemical compound CC1(C(C(C(C2=CC(=CC=C12)C(=CC1=CC=C(C=C1)C1=NN=NN1)C)(C)C)=O)=O)C ITKWEXDHDYDKPX-UHFFFAOYSA-N 0.000 description 1
- UOWBTUCZKXIARD-UHFFFAOYSA-N 1,1,4,4-tetramethyl-7-[1-[4-(2h-tetrazol-5-yl)phenyl]but-1-en-2-yl]-3h-naphthalen-2-one Chemical compound C=1C=C(C(CC(=O)C2(C)C)(C)C)C2=CC=1C(CC)=CC(C=C1)=CC=C1C=1N=NNN=1 UOWBTUCZKXIARD-UHFFFAOYSA-N 0.000 description 1
- MIXOXEMYCDHUOI-UHFFFAOYSA-N 1,1,4,4-tetramethyl-7-[1-[4-(2h-tetrazol-5-yl)phenyl]prop-1-en-2-yl]-3h-naphthalen-2-one Chemical compound C=1C=C(C(CC(=O)C2(C)C)(C)C)C2=CC=1C(C)=CC(C=C1)=CC=C1C=1N=NNN=1 MIXOXEMYCDHUOI-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- UMENQXHZHWFBGB-UHFFFAOYSA-N 5-[3-[2-(1,1,3,3-tetramethyl-2H-inden-5-yl)prop-1-enyl]phenyl]-2H-tetrazole Chemical compound CC1(CC(C2=CC(=CC=C12)C(=CC1=CC(=CC=C1)C1=NN=NN1)C)(C)C)C UMENQXHZHWFBGB-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
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- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
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- 208000010011 Vitamin A Deficiency Diseases 0.000 description 1
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- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
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- 150000001983 dialkylethers Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
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- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
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- 210000002268 wool Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
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- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Description
Foreliggende oppfinnelse vedrører fremstilling av nye vinyl-tetrazolfenylderivater. The present invention relates to the production of new vinyl-tetrazolephenyl derivatives.
Fra tysk OS 28 54 354 og 32 02 118 er det f.eks. kjent at vinylbenzosyrederivater har farmakologiske virkninger ved topisk og systemisk terapi av neoplasier, akne, psoriasis og andre dermatologiske forstyrrelser. Disse vinylbenzosyrederivatene er imidlertid ikke alltid tilfredsstillende. Fremfor alt er deres utpregede toksiske (bi)virkning uheldig, hvilke gjør disse forbindelser lite egnet som middel i topisk og systemisk terapi av neoplasier, akne, psoriasis og andre dermatologiske forstyrrelser. Det uheldige ved forbindelsene fra tysk OS 28 54 354 beskrives f.eks. av A. Kistler i Calcified Tissue International 33, 249-254 (1981) og viser seg ved flere gangers applikasjon på gnagere ifølge den metodikk som er beskrevet av R. C. Moon et al i Cancer Research 39, 1339-1346 (1979). From German OS 28 54 354 and 32 02 118 there is e.g. known that vinylbenzoic acid derivatives have pharmacological effects in topical and systemic therapy of neoplasias, acne, psoriasis and other dermatological disorders. However, these vinylbenzoic acid derivatives are not always satisfactory. Above all, their pronounced toxic (side) effect is unfortunate, which makes these compounds unsuitable as agents in topical and systemic therapy of neoplasias, acne, psoriasis and other dermatological disorders. The unfortunate aspect of the connections from German OS 28 54 354 is described, for example. by A. Kistler in Calcified Tissue International 33, 249-254 (1981) and is shown by repeated application to rodents according to the methodology described by R. C. Moon et al in Cancer Research 39, 1339-1346 (1979).
Oppgaven for foreliggende oppfinnelse er å tilveiebringe forbindelser med sammenlignbar virkningsgrad og mindre toksiske bivirkninger. The task of the present invention is to provide compounds with comparable effectiveness and less toxic side effects.
Man har nå funnet at vinyltetrazolylfenylderivater medIt has now been found that vinyltetrazolylphenyl derivatives with
formel (I)formula (I)
hvori R 1 og R 2 er hydrogen eller en metylgruppe, wherein R 1 and R 2 are hydrogen or a methyl group,
3 4 3 4
R og R hydrogen, halogen, en C^_^-alkyl eller C-^_^-alkoksy-gruppe, R and R hydrogen, halogen, a C^_^-alkyl or C-^_^-alkyl group,
R^ hydrogen, en C^_g-alkyl- eller en C-^g-cykloalkylgruppe ogR 1 is hydrogen, a C 1-6 alkyl group or a C 1-6 cycloalkyl group and
A en likeledes med C, .-alkylgruppe substituert metylen- ellerA likewise with C, .-alkyl group substituted methylene- or
1 2 1 2
etylenrest eller - når R og R utgjør metylgrupper - også betyr ethylene residue or - when R and R form methyl groups - also means
restene -CH2-C0- eller -Cr^-CH-, og deres fysiologisk fordragelige salter egner seg godt for behandling av sykdommer. the residues -CH2-C0- or -Cr^-CH-, and their physiologically tolerable salts are well suited for the treatment of diseases.
Som den bølgeformige viste C-H-binding i formel I angir,As the wavy C-H bond shown in formula I indicates,
kan forbindelsene fremstilt ifølge oppfinnelsen foreligge i can the compounds prepared according to the invention be present in
cis-(Z)- eller trans-(E)-formen. Trans-E-formene er foretrukne. Som foretrukket alkylgruppe på A må metylgruppen nevnes. For the cis-(Z) or trans-(E) form. The Trans-E forms are preferred. The methyl group must be mentioned as the preferred alkyl group on A. For
3 4 5 3 4 5
R og R er hydrogen, metyl og metoksy foretrukket. R er fortrinnsvis hydrogen eller metyl. R and R are preferably hydrogen, methyl and methoxy. R is preferably hydrogen or methyl.
Typiske eksempler på forbindelser ifølge oppfinnelsen er foruten de substanser som er nevnt i eksemplene: 2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1- £4-(lH-tetrazol-5-yl)fenylj -eten Typical examples of compounds according to the invention are, in addition to the substances mentioned in the examples: 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-£4- (1H-tetrazol-5-yl)phenylj -ethene
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(lH-tetrazol-5-yl)fenylj-eten 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenylj-ethene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1- U~2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1- U~
(lH-tetrazol-5-yl)fenyl} -1-buten (1H-tetrazol-5-yl)phenyl}-1-butene
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(lH-tetrazol-5-yl)f enyl]-1-buten 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-butene
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)f enyl]-1-buten 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-butene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-T4-(lH-tetrazol-5-yl)fenyl]-1-octen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-T4-(1H-tetrazol-5-yl)phenyl]-1-octene
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-f4-(lH-tetrazol-5-yl)fenyl}-1-octen 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-f4-(1H-tetrazol-5-yl)phenyl}-1-octene
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)fenylj-1-octen 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenylj-1-octene
2-(1,1,4,4,7-Pentametyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen 2-(1,1,4,4,7-Pentamethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-propene
2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(lH-tetrazol-5-yl)fenyl}-1-propen 2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(1H-tetrazol-5-yl)phenyl}-1-propene
2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-1^4-(lH-tetrazol-5-yl)fenylj -1-propen 2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl)-1^4-(1H-tetrazol-5-yl)phenylj -1-propene
2-(7-Etyl-l,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl) 2-(7-Ethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)
-l-[4- (lH-tetrazol-5-yl)fenyl}-1-propen -1-[4-(1H-tetrazol-5-yl)phenyl}-1-propene
2-(6-Etyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-f4-(lH-tetrazol-5-yl)fenyj-1-propen 2-(6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl-1-propene
2-(6-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl) 2-(6-Ethyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)
-l-£4-(lH-tetrazol-5-yl)f enyl] -1-propen -1-£4-(1H-tetrazol-5-yl)phenyl]-1-propene
2-[7-(2)-Metyletyl)-1,1,4,4-tetrametyl-l,2,3,4-tetrahydronaf t-6-yl] -1-C4-(lH-tetrazol-5-yl)fenyl} -1-propen 2-[7-(2)-Methylethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl]-1-C4-(1H-tetrazol-5-yl )phenyl}-1-propene
2-T6-(2-Metyletyl)-1,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)-1-C4-(lH-tetrazol-5-yl)fenyl3-1-propen 2-[6-(2-Metyletyl)-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)- 2-T6-(2-Methylethyl)-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-C4-(1H-tetrazol-5-yl)phenyl3 -1-propene 2-[6-(2-Methylethyl)-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-
indenyl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-X3-lH-tetrazol-5-yl)fenyl} -1-propen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-X3-1H-tetrazol-5-yl)phenyl}-1-propene
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-[3-(1H-tetrazol-5-yl)fenyl] -1-propen 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[3-(1H-tetrazol-5-yl)phenyl]-1-propene
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T3-(1H-tetrazol-5-yl)fenyl]-1-propen 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-T3-(1H-tetrazol-5-yl)phenyl]-1-propene
2-(7-butyl-l,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenylj-1-propen 2-(7-butyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenylj-1- propene
2-(6-Butyl-l,1,3,3-tetrametyl-2,3-dihydro-5(lH-indenyl)-1--[4-(lH-tetrazol-5-yl)fenyl}-1-propen 2-(6-Butyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl}-1- propene
2-(6-Butyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)-l-£4-(lH-tetrazol-5-yl)fenyl]-1-propen 2-(6-Butyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-£4-(1H-tetrazol-5-yl)phenyl]- 1-propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-2-cyklo-propyl-l-f4-(lH-tetrazol-5-yl)f enyl}eten 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-cyclopropyl-1-[4-(1H-tetrazol-5-yl)phenyl} the food
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l~C4-(lH-tetrazol-5-yl)fenyl] -eten 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl-1~C4-(1H-tetrazol-5-yl)phenyl]-ethene
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l-t 4-tetrazol-5-yl)fenyl] -eten 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclo-propyl-1-t 4-tetrazol-5-yl)phenyl]-ethene
2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklopropyl-l-t4-(lH-tetrazol-5-yl)fenyl]-eten 2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl-1-t4-(1H-tetrazol-5-yl)phenyl] - the ethene
2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l-[4-(lH-tetrazol-5-yl)fenyl] -1- [4-(lH-tetrazol-5-yl)-fenyl} -eten 2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl-1-[4-(1H-tetrazol-5-yl)phenyl ] -1-[4-(1H-tetrazol-5-yl)-phenyl}-ethene
2- r (1,1, 3 , 3 , 7-Pentametyl-l ,2,3, 4-tetrahydronaf t-6-yl) -2-cyklo-propyl-l-[4-(lH-tetrazol-5-yl)fenyl}-1- Ia-(lH-tetrazol-5-yl)-fenyl] -eten 2- r (1,1,3,3,7-Pentamethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-cyclopropyl-1-[4-(1H-tetrazol-5- yl)phenyl}-1-1a-(1H-tetrazol-5-yl)-phenyl]-ethene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-T4-(lH-tetrazol-5-yl)fenyl]-(3-metyl)-buten-1 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-T4-(1H-tetrazol-5-yl)phenyl]-(3-methyl)- butene-1
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)fenyl} -(3-metyl)-buten-1 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(1H-tetrazol-5-yl)phenyl}-(3-methyl)- butene-1
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(lH-tetrazol-5-yl)fenyl]-(3-metyl)-buten-1 2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(1H-tetrazol-5-yl)phenyl]-(3-methyl) -butene-1
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-heksyl-l-f4-(lH-tetrazol-5-yl)fenyl} -eten 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclohexyl-1-f4-(1H-tetrazol-5-yl)phenyl}-ethene
2-(1,1,2,,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-heksyl-l-C4-(lH-tetrazol-5-yl)fenyl] -eten 2-(1,1,2,,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclohexyl-1-C4-(1H-tetrazol-5-yl)phenyl ] -ethene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-2-cyklo-heksyl-l-[4-(lH-tetrazol-5-yl)fenyl] -eten 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-2-cyclohexyl-1-[4-(1H-tetrazol-5-yl)phenyl] - the ethene
2-(4,4,7-Trimetyl-l,2,3,4-tetrahydronaft-6-yl)-1-[4-(1H-tetrazol-5-yl)fenyl] -1-propen 2-(4,4,7-Trimethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1-propene
2-(4,4-Dimetyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetra-zol-5-yl) fenyl] -1-propen 2-(4,4-Dimethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetra-zol-5-yl)phenyl]-1-propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2-oxo-naphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl] -1-propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2,3-diokso-naft-6-yl)-1-[4-(lH-tetrazol-5-yl)fenyl] -1-propen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2,3-dioxo-naphth-6-yl)-1-[4-(1H-tetrazol-5-yl) phenyl]-1-propene
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-2-okso-indenyl)-1--£4-(lH-tetrazol-5-yl)fenyl]-1-propen 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-2-oxo-indenyl)-1--£4-(1H-tetrazol-5-yl)phenyl]-1 -propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl ]-1-propene
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-2-hydroksy-indenyl)--l-[4-(lH-tetrazol-5-yl)fenyl] -1-propen 2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-2-hydroxy-indenyl)--1-[4-(1H-tetrazol-5-yl)phenyl]-1 -propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2-hydroksy-naft--6yl)-l-t 4-(lH-tetrazol-5-yl)fenyl]-1-propen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2-hydroxy-naphth--6yl)-1-t 4-(1H-tetrazol-5-yl)phenyl]-1- propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-hydroksy-naft--6-yl) -l-["4- (lH-tetrazol-5-yl) fenyl] -1-propen 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-hydroxy-naphth--6-yl)-1-["4-(1H-tetrazol-5-yl) phenyl]-1-propene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl}-eten 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-2-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl }-ethene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-eten 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl ]-ethene
2-(1,1,4,4-Tetraetyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)--1-T4-(lH-tetrazol-5-yl)fenyl]-1-buten 2-(1,1,4,4-Tetraethyl-1,2,3,4-tetrahydro-2-oxo-naphth-6-yl)--1-T4-(1H-tetrazol-5-yl)phenyl] -1-butene
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-1-buten 2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydro-3-oxo-naphth-6-yl)--1-[4-(1H-tetrazol-5-yl)phenyl ]-1-butene
Forbindelsene fremstilles ifølge oppfinnelsen ved omsetning av et azid med et nitril med formel (II) The compounds are prepared according to the invention by reacting an azide with a nitrile of formula (II)
1 2 3 4 5 1 2 3 4 5
hvori R , R , R , R , R og A har de ovenfor angitte betydninger. wherein R , R , R , R , R and A have the meanings given above.
Omsetningen med azidet under tetrazoldannelse forløper ved en temperatur fra ca. romtemperatur til ca. 200°C, fortrinnsvis ved 60 til 100°C. Omsetningen kan finne sted ved normalt trykk eller i lukket apparatur under forhøyet trykk, hensiktsmessig under oppvarming til det angitte temperaturområdet. The reaction with the azide during tetrazole formation proceeds at a temperature from approx. room temperature to approx. 200°C, preferably at 60 to 100°C. The reaction can take place at normal pressure or in a closed apparatus under elevated pressure, suitably during heating to the indicated temperature range.
Hensiktsmessig foretas omsetningen i nærvær av et fortyn-nings- eller løsningmiddel, f.eks. en av de lavere mettede dialkyletere, dialkylglykoletere eller cykliske etere, såsom dietyleter, etyl-tert.-butyleter, 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et aromatisk hydrokarbon, såsom benzen eller et alkylbenzen, såsom toluen eller xylen, eller et mettet alifa-tisk hydrokarbon, såsom heksan, heptan eller isooctan, et alkyl-formamid, såsom dimetyl- eller dietylformamid, i protiske løs-ningsmidler såsom alkoholer eller i blandinger av de nevnte løs-ningsmidler. Fortrinnsvis anvender man cykliske etere, såsom dioksan eller tetrahydrofuran samt spesielt dimetylformamid eller blandinger derav, hvorunder omsetningen generelt forløper ved en temperatur fra 60 til 100°C. Appropriately, the turnover is carried out in the presence of a diluent or solvent, e.g. one of the lower saturated dialkyl ethers, dialkyl glycol ethers or cyclic ethers, such as diethyl ether, ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene or an alkylbenzene such as toluene or xylene, or a saturated aliphatic hydrocarbon, such as hexane, heptane or isooctane, an alkyl formamide, such as dimethyl or diethylformamide, in protic solvents such as alcohols or in mixtures of the aforementioned solvents. Cyclic ethers, such as dioxane or tetrahydrofuran and especially dimethylformamide or mixtures thereof, are preferably used, during which the reaction generally proceeds at a temperature from 60 to 100°C.
Det anbefales å foreta omsetningen i nærvær av et uorganisk halogenid. Som uorganiske halogenider kommer ammoniumklorid, litiumklorid, aluminium(III)klorid spesielt på tale. It is recommended to carry out the reaction in the presence of an inorganic halide. As inorganic halides, ammonium chloride, lithium chloride, aluminum (III) chloride are particularly relevant.
Som azider kommer fortrinnsvis alkaliazider, såsom litium-azid, natriumazid eller kaliumazid, fortrinnsvis natriumazid eller 1,1,3,3-tetrametylguanidiniumazid i betraktning. As azides, alkali azides, such as lithium azide, sodium azide or potassium azide, preferably sodium azide or 1,1,3,3-tetramethylguanidinium azide, come into consideration.
Utgangsforbindelsene med formel (II) kan enhetlig ha cis-eller transstruktur eller være blandinger av de to E-/Z-isomere. En isomerisering ved fremstilling av de nye forbindelser i sterisk enhetlig form kan ikke utelukkes. Isomerblandingen som dannes i slike tilfeller av forbindelsene med formel (I) fremstilt ifølge oppfinnelsen kan bestemmes kvantitativt ved HPLC-13 The starting compounds of formula (II) can uniformly have a cis- or trans-structure or be mixtures of the two E-/Z-isomers. An isomerization during the production of the new compounds in sterically uniform form cannot be ruled out. The isomer mixture formed in such cases by the compounds of formula (I) produced according to the invention can be determined quantitatively by HPLC-13
analyse eller med et C-NMR-spektrum, og den ønskede isomere eventuelt isoleres ved fraksjonert krystallisering eller kromato-grafi med f.eks. kiselgelsøyler eller med preparativ HPLC-kroma-tografi i ren form. analysis or with a C-NMR spectrum, and the desired isomer is optionally isolated by fractional crystallization or chromatography with e.g. silica gel columns or with preparative HPLC chromatography in pure form.
Fremstillingen av utgangsnitrilene med formel (II) er beskrevet i tysk OS 32 02 125 eller kan fremstilles etter den deri angitte arbeidsforskrift. For eksempel kan en karbonylforbindel-se med formel (III) hvori R"1", R^, R^, R4, R5 og A har de ovenfor angitte betydninger omsettes med en para- eller meta-substituert fosforforbindel-se formel (IV) The preparation of the starting nitriles with formula (II) is described in German OS 32 02 125 or can be prepared according to the work regulations specified therein. For example, a carbonyl compound of formula (III) in which R"1", R^, R^, R4, R5 and A have the above meanings can be reacted with a para- or meta-substituted phosphorus compound of formula (IV)
i en Horner-Emmons-reaksjon. in a Horner-Emmons reaction.
Forbindelsen fremstilt ifølge oppfinnelsen er et surt hydrogenatom på tetrazolringen og kan derfor med base på vanlig måte overføres i et fysiologisk fordragelig, vannløselig salt. Egnede salter er f. eks. ammonium-y alkalimetall- (spesielt nat-rium, kalium og litium) og jordalkalimetallsalter, spesielt av kalsium eller magnesium samt salter med egnede organiske baser såsom ved lavere alkylaminer, f.eks. metylamin eller etylamin, med substituerte lavere alkylaminer, spesielt hydroksysubstituer-te alkylaminer såsom dietanolamin, trietanolamin eller tris-hydroksymetylaminometan, piperidin eller morfolin. The compound produced according to the invention has an acidic hydrogen atom on the tetrazole ring and can therefore be transferred with a base in the usual way in a physiologically tolerable, water-soluble salt. Suitable salts are e.g. ammonium-y alkali metal (especially sodium, potassium and lithium) and alkaline earth metal salts, especially of calcium or magnesium as well as salts with suitable organic bases such as with lower alkylamines, e.g. methylamine or ethylamine, with substituted lower alkylamines, especially hydroxy-substituted alkylamines such as diethanolamine, triethanolamine or tris-hydroxymethylaminomethane, piperidine or morpholine.
Forbindelsen fremstilt ifølge oppfinnelsen og deres fysio-logiske fordragelige salter kan på grunn av deres farmakologiske egenskaper anvendes ved en topisk og systemisk terapi og også profylakse av prekanzeroser og karzinomer i huden, slimhinnene og innvendige organer samt ved topisk og systemisk terapi av akne, psoriasis og andre dermatologiske sykdommer som har forbindelse med patologisk forandret horndannelse samt ved behandling av revmatiske sykdommer, spesielt slike av betennelses-eller degenerativ type som angriper ledd, muskler, sener og andre deler av bevegelsesapparatet. Foretrukne indikasjonsom-råder er ved siden av terapi av dermatologiske sykdommer den profylaktiskeog terapeutiske behandling av prekanzeroser og tumorer, samt behandling av artritiske sykdommer. Den dermatologiske aktivitet, f.eks. for behandling av akne, kan blant annet påvises ved bestemmelse av den komedolytiske aktivitet og evnen til å redusere antall utrikuli i Rhino-mus modellen. Denne metoden er beskrevet av L.H. Kligman et al. i The Journal of Investigative Dermatology 73, 354 til 38 (1979) og av J.A. Mezick et al. i "Models of Dermatology (Ed. Maibach, Lowe) Vol. 2, s. 59-63, Karger, Basch 1985. Antiartritisk virkningen til forbindelsen fremstilt ifølge oppfinnelsen kan bestemmes på vanlig måte i dyre-eksperiment i Adjuvans-artritis-modellen. Den preventive virkning ved dannelse og utvikling av premalig-gende lesjoner kan f.eks. påvises i de etterfølgende forsøks-modeller. Forbindelsen fremstilt ifølge oppfinnelsen opphever på hamster-treakealvev in vitro keratiniseringen som begynner ved vitamin-A-mangel. Denne keratiniseringen tilhører en tidlig fase av karcinogenese som i en lignende teknikk in vivo etter initiering med kjemiske forbindelser inhiberes ved energirik stråling eller etter virale celletransformasjoner med forbindelsen med formel (I) fremstilt ifølge foreliggende oppfinnelse. Denne metodikken kan man lese i Cancer Res. 36, 96 4 til 972 The compound produced according to the invention and their physiologically tolerable salts can, due to their pharmacological properties, be used in topical and systemic therapy and also in the prophylaxis of precancers and carcinomas in the skin, mucous membranes and internal organs as well as in topical and systemic therapy of acne, psoriasis and other dermatological diseases that have a connection with pathologically changed horn formation as well as in the treatment of rheumatic diseases, especially those of an inflammatory or degenerative type that attack joints, muscles, tendons and other parts of the locomotor system. Preferred indication areas are, in addition to the therapy of dermatological diseases, the prophylactic and therapeutic treatment of precancers and tumors, as well as the treatment of arthritic diseases. The dermatological activity, e.g. for the treatment of acne, can be demonstrated, among other things, by determining the comedolytic activity and the ability to reduce the number of utriculi in the Rhino mouse model. This method is described by L.H. Kligman et al. in The Journal of Investigative Dermatology 73, 354 to 38 (1979) and by J.A. Mezick et al. in "Models of Dermatology (Ed. Maibach, Lowe) Vol. 2, pp. 59-63, Karger, Basch 1985. The antiarthritic effect of the compound prepared according to the invention can be determined in the usual way in animal experiments in the Adjuvant arthritis model. The preventive effect on the formation and development of premalignant lesions can, for example, be demonstrated in the following experimental models. The compound produced according to the invention cancels in vitro the keratinization that begins with vitamin A deficiency in hamster treacal tissue. This keratinization belongs to a early phase of carcinogenesis which in a similar technique in vivo after initiation with chemical compounds is inhibited by high-energy radiation or after viral cell transformations with the compound of formula (I) prepared according to the present invention. This methodology can be read in Cancer Res. 36, 96 4 to 972
(1976) eller i Nature 250, 64 til 66 (1974) og Nature 253, 47 til 50 (1975). (1976) or in Nature 250, 64 to 66 (1974) and Nature 253, 47 to 50 (1975).
Dertil inhiberes formeringshastigheten til bestemte ond-artede forandrede celler ved forbindelsen fremstilt ifølge oppfinnelsen. Denne metodikken fremgår av J. Nati. Cancer Inst. 60, 1035 til 1041 (1978), Experimental Cell Research 117, 15 til 22 (1978) og Proe. Nati.Acad.Sei.USA 77, 2936 til 2940 (1980). Videre vises til bestemmelsen av de antagonistiske virkningene overfor forbolester som beskrives i Cancer Res. 37, 2196 til 2201 (1977). In addition, the rate of reproduction of certain malignantly altered cells is inhibited by the compound produced according to the invention. This methodology appears from J. Nati. Cancer Inst. 60, 1035 to 1041 (1978), Experimental Cell Research 117, 15 to 22 (1978) and Proe. Nati.Acad.Sei.USA 77, 2936 to 2940 (1980). Reference is also made to the determination of the antagonistic effects against phorbol esters described in Cancer Res. 37, 2196 to 2201 (1977).
Som terapeutiske midler for topisk og systemisk anvendelse blandes en forbindelse med formel (I) med vanlig bærestoffer eller fortynningsmidler og kan anvendes ved bekjempelse av sykdommer . As therapeutic agents for topical and systemic use, a compound of formula (I) is mixed with usual carriers or diluents and can be used in combating diseases.
Fremstillingen av de terapeutiske midler eller preparater skjer med de vanlige flytende eller faste bærestoffer eller fortynningsmidler og de på vanlig måte anvendte farmasøytiske tekniske hjelpestoffer avhengig av den ønskede applikasjonstype og med en egnet dosering for anvendelsen på vanlig måte, f.eks. ved blanding av virkestoffet med de vanlige faste eller flytende bære- og hjelpestoffer i slike preparater. The production of the therapeutic agents or preparations takes place with the usual liquid or solid carriers or diluents and the normally used pharmaceutical technical aids depending on the desired type of application and with a suitable dosage for the use in the usual way, e.g. by mixing the active substance with the usual solid or liquid carriers and auxiliary substances in such preparations.
Midlene kan følgelig gis peroralt, parenteralt eller topisk. Slike preparater er f.eks. tabletter, filmtabletter, drageer, kapsler, piller, pulvere, løsninger eller suspensjoner, infusjons-eller injeksjonsløsninger samt pastaer, salver, geleer,kremer, lotioner, puddere, løsninger eller emulsjoner og sprays. The agents can therefore be administered orally, parenterally or topically. Such preparations are e.g. tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, infusion or injection solutions as well as pastes, ointments, gels, creams, lotions, powders, solutions or emulsions and sprays.
De terapeutiske midler kan inneholde forbindelsene fremstilt ifølge foreliggende oppfinnelse ved lokale anvendelser i 0,001 til 1%-ig konsentrasjoner, fortrinnsvis i 0,001 til 0,1%- The therapeutic agents can contain the compounds prepared according to the present invention for local applications in 0.001 to 1% concentrations, preferably in 0.001 to 0.1%
ig konsentrasjon og ved systemiske anvendelser fortrinnsvis i en enkel dose på 0,1 til 50 mg, og gis daglig i en eller flere doser avhengig av sykdommens art og grad. ig concentration and for systemic applications preferably in a single dose of 0.1 to 50 mg, and given daily in one or more doses depending on the nature and degree of the disease.
Vanlig anvendte farmasøytiske tekniske hjelpestoffer er f.eks. for lokale anvendelser.alkoholer, såsom isopropanol, oksetylert ricinusolje eller oksetylert hydrogenert ricinusolje, polyakrylsyre, glycerolmonostearat, paraffinolje, vaseliner, ullfett, polyetylenglykol 400, polyetylenglykol 400-stearat samt etoksylert fettalkohol, for systemiske anvendelser melke-sukker, propylenglykol og etanol, stivelse, talkum, polyvinyl-pyrrolidon. Preparatene kan eventuelt tilsettes et antioksida-sjonsmiddel, f.eks. tokoferol samt butylert hydroksyanisol eller butylert hydroksytoluen eller smaksforbedrende tilsetninger, stabiliseringsmidler, emulgeringsmidler, glidemidler osv. En forutsetning er at alle stoffer som anvendes ved fremstillingen av de farmasøytiske preparater er toksikologisk ubetenkelige og forenelige med de anvendte virkestoffer. Commonly used pharmaceutical technical aids are e.g. for local applications. alcohols, such as isopropanol, oxytylated castor oil or oxytylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, petroleum jelly, wool fat, polyethylene glycol 400, polyethylene glycol 400 stearate and ethoxylated fatty alcohol, for systemic applications milk sugar, propylene glycol and ethanol, starch, talc, polyvinyl pyrrolidone. The preparations can optionally have an antioxidant added, e.g. tocopherol as well as butylated hydroxyanisole or butylated hydroxytoluene or taste-improving additives, stabilizers, emulsifiers, lubricants, etc. A prerequisite is that all substances used in the manufacture of the pharmaceutical preparations are toxicologically harmless and compatible with the active substances used.
De følgende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.
Eksempel 1 Example 1
(E)-2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-[4-(lH-tetrazol-5-yl)fenyl]-1-propen (E)-2-(1,1,4,4-Tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1-[4-(1H-tetrazol-5-yl)phenyl]-1 -propene
Til en suspensjon av 65 g natriumazid i 500 ml tetrahydrofuran innførtes ved 0°C i små porsjoner 33,5 g vannfritt alumi-niumklorid. Deretter oppvarmet man ca. 4 5 minutter ved tilbake-løp, blandet med 16,5 g (E)-4-£2-(5,6,7,8-tetrahydro-5,5,8,8-tetrametyl-2-naftalenyl)-1-propenyl]-benzonitril og rørte deretter igjen 24 timer ved tilbakeløpstemperatur. Etter avkjølin-gen ble reaksjonsblandingen helt på 2,5 1 isvann, blandet med 250 ml etanol og surgjort med 2 N saltsyre. Det dannede faste stoff ble filtrert fra og vasket på filteret med 100 ml kald metanol. Etter tørking i nitrogenstrøm ble 12,2 g (66% d.Th.) (E)-2-(1,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1- [4-(1H-tetrazol-5-yl)fenyl]-1-propen, smp. 227 til 230°C tilbake.<13>C-NMR-spektrumet viser at det dreier seg om den isomerrene tittel-forbindelse i trans-konfigurasjon. To a suspension of 65 g of sodium azide in 500 ml of tetrahydrofuran, 33.5 g of anhydrous aluminum chloride were introduced at 0° C. in small portions. Then heated approx. 4 5 minutes at reflux, mixed with 16.5 g of (E)-4-£2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1 -propenyl]-benzonitrile and then stirred again for 24 hours at reflux temperature. After cooling, the reaction mixture was poured into 2.5 l of ice water, mixed with 250 ml of ethanol and acidified with 2 N hydrochloric acid. The solid formed was filtered off and washed on the filter with 100 ml of cold methanol. After drying in a stream of nitrogen, 12.2 g (66% d.Th.) (E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-6-yl)-1 - [4-(1H-tetrazol-5-yl)phenyl]-1-propene, m.p. 227 to 230°C back.<13>C-NMR spectrum shows that it is the isomerically pure title compound in trans configuration.
Analogt ble substansene i den etterfølgende tabell fremstilt . Analogously, the substances in the following table were prepared.
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JP (1) | JPS6185371A (en) |
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DE (1) | DE3434948A1 (en) |
FI (1) | FI853621L (en) |
HU (1) | HU192363B (en) |
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DE3434944A1 (en) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | L-SUBSTITUTED TETRALIN DERIVATIVES, THEIR PRODUCTION AND USE |
AU587994B2 (en) * | 1984-09-27 | 1989-09-07 | Processing Technologies International Limited | Low alcohol wine |
ZW7487A1 (en) * | 1986-05-23 | 1987-12-16 | Hoffmann La Roche | Tetrahydronaphthaline and indane derivatives |
US5030764A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
US5030765A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
AT388728B (en) * | 1987-03-17 | 1989-08-25 | Hoffmann La Roche | NEW TETRAHYDRONAPHTHALINE AND INDANDERIVATIVES |
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EP0084667B1 (en) * | 1982-01-23 | 1985-09-18 | BASF Aktiengesellschaft | Phenylethylene derivatives, their preparation and use as medicines |
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1984
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HUT39434A (en) | 1986-09-29 |
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