NO853694L - Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav. - Google Patents
Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav.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
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 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
- 208000005328 Viral Cell Transformation Diseases 0.000 description 1
- 208000010011 Vitamin A Deficiency Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002456 anti-arthritic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 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
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000002995 comedolytic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 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
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 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
- 239000008298 dragée Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- YCOZIPAWZNQLMR-UHFFFAOYSA-N heptane - octane Natural products CCCCCCCCCCCCCCC YCOZIPAWZNQLMR-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 230000003137 locomotive effect Effects 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 1
- 150000004633 phorbol derivatives Chemical class 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940066769 systemic antihistamines substituted alkylamines 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
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- 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
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører fremstilling av nye vinyl-tetrazolfenylderivater.
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).
Oppgaven for foreliggende oppfinnelse er å tilveiebringe forbindelser med sammenlignbar virkningsgrad og mindre toksiske bivirkninger.
Man har nå funnet at vinyltetrazolylfenylderivater med
formel (I)
hvori R 1 og R 2 er hydrogen eller en metylgruppe,
3 4
R og R hydrogen, halogen, en C^_^-alkyl eller C-^_^-alkoksy-gruppe,
R^ hydrogen, en C^_g-alkyl- eller en C-^g-cykloalkylgruppe og
A en likeledes med C, .-alkylgruppe substituert metylen- eller
1 2
etylenrest eller - når R og R utgjør metylgrupper - også betyr
restene -CH2-C0- eller -Cr^-CH-, og deres fysiologisk fordragelige salter egner seg godt for behandling av sykdommer.
Som den bølgeformige viste C-H-binding i formel I angir,
kan forbindelsene fremstilt ifølge oppfinnelsen foreligge i
cis-(Z)- eller trans-(E)-formen. Trans-E-formene er foretrukne. Som foretrukket alkylgruppe på A må metylgruppen nevnes. For
3 4 5
R og R er hydrogen, metyl og metoksy foretrukket. R er fortrinnsvis hydrogen eller metyl.
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
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(lH-tetrazol-5-yl)fenylj-eten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1- U~
(lH-tetrazol-5-yl)fenyl} -1-buten
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-[4-(lH-tetrazol-5-yl)f enyl]-1-buten
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)f enyl]-1-buten
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-T4-(lH-tetrazol-5-yl)fenyl]-1-octen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-f4-(lH-tetrazol-5-yl)fenyl}-1-octen
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)fenylj-1-octen
2-(1,1,4,4,7-Pentametyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T4-(lH-tetrazol-5-yl)fenyl}-1-propen
2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-1^4-(lH-tetrazol-5-yl)fenylj -1-propen
2-(7-Etyl-l,1,4,4-tetrametyl-l,2,3,4-tetrahydronaft-6-yl)
-l-[4- (lH-tetrazol-5-yl)fenyl}-1-propen
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-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)
-l-£4-(lH-tetrazol-5-yl)f enyl] -1-propen
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-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)-
indenyl)-l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-X3-lH-tetrazol-5-yl)fenyl} -1-propen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-[3-(1H-tetrazol-5-yl)fenyl] -1-propen
2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-T3-(1H-tetrazol-5-yl)fenyl]-1-propen
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-(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-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)-l-£4-(lH-tetrazol-5-yl)fenyl]-1-propen
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-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl-l~C4-(lH-tetrazol-5-yl)fenyl] -eten
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-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklopropyl-l-t4-(lH-tetrazol-5-yl)fenyl]-eten
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- 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-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-T4-(lH-tetrazol-5-yl)fenyl]-(3-metyl)-buten-1
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-l-[4-(lH-tetrazol-5-yl)fenyl} -(3-metyl)-buten-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-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-heksyl-l-f4-(lH-tetrazol-5-yl)fenyl} -eten
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-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-2-cyklo-heksyl-l-[4-(lH-tetrazol-5-yl)fenyl] -eten
2-(4,4,7-Trimetyl-l,2,3,4-tetrahydronaft-6-yl)-1-[4-(1H-tetrazol-5-yl)fenyl] -1-propen
2-(4,4-Dimetyl-l,2,3,4-tetrahydronaft-6-yl)-l-[4-(lH-tetra-zol-5-yl) fenyl] -1-propen
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-Tetrametyl-l,2,3,4-tetrahydro-2,3-diokso-naft-6-yl)-1-[4-(lH-tetrazol-5-yl)fenyl] -1-propen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-2-okso-indenyl)-1--£4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-2-hydroksy-indenyl)--l-[4-(lH-tetrazol-5-yl)fenyl] -1-propen
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-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-Tetrametyl-l,2,3,4-tetrahydro-2-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl}-eten
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-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-Tetrametyl-l,2,3,4-tetrahydro-3-okso-naft-6-yl)--l-[4-(lH-tetrazol-5-yl)fenyl]-1-buten
Forbindelsene fremstilles ifølge oppfinnelsen ved omsetning av et azid med et nitril med formel (II)
1 2 3 4 5
hvori R , R , R , R , R og A har de ovenfor angitte betydninger.
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.
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.
Det anbefales å foreta omsetningen i nærvær av et uorganisk halogenid. Som uorganiske halogenider kommer ammoniumklorid, litiumklorid, aluminium(III)klorid spesielt på tale.
Som azider kommer fortrinnsvis alkaliazider, såsom litium-azid, natriumazid eller kaliumazid, fortrinnsvis natriumazid eller 1,1,3,3-tetrametylguanidiniumazid i betraktning.
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
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.
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)
i en Horner-Emmons-reaksjon.
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.
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
(1976) eller i Nature 250, 64 til 66 (1974) og Nature 253, 47 til 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).
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 .
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.
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.
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%-
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.
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.
De følgende eksempler illustrerer oppfinnelsen.
Eksempel 1
(E)-2-(1,1,4,4-Tetrametyl-l,2,3,4-tetrahydronaft-6-yl)-1-[4-(lH-tetrazol-5-yl)fenyl]-1-propen
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.
Analogt ble substansene i den etterfølgende tabell fremstilt .
Claims (2)
1. Fremgangsmåte ved fremstilling av vinyltetrazolylfenylderivater med formel (I)
1 2
hvor R og R er hydrogen eller en metylgruppe,
R 3 og R 4hydrogen, halogen, en C^ _^ -alkyl eller C^ _^ -alkoksy-gruppe,
R 5hydrogen, en C^ _g-alkyl- eller en C-^ g-cykloalkylgruppe og A en eventuelt med C,_4 -alkylgruppe substituert metylen-eller etylenrest, eller - når R 1 09q§ 2 er metylgruppe - også betyr restene -Cr^-CO- eller -Cr^ -CH-, og deres fysiologisk fordragelige salter, karakterisert ved at man omset-ter et azid med et nitril med formel (II)
1 2 3 4 5
hvori R , R , R , R , R og A har de ovenfor angitte betydninger .
2. Fremgangsmåte ifølge krav 1, ved fremstilling av forbindelse med formel (I) som foreligger i E-form og hvori R 1 og R 2 har 3 4
de forutangitte betydninger og R og R betyr hydrogen, metyl og/eller metoksy og R hydrogen eller metyl, karakterisert ved at man anvender tilsvarende substituerte utgangsforbindelser.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843434948 DE3434948A1 (de) | 1984-09-22 | 1984-09-22 | Vinyltetrazolylphenyl-derivate, ihre herstellung und verwendung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO853694L true NO853694L (no) | 1986-03-24 |
Family
ID=6246164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO853694A NO853694L (no) | 1984-09-22 | 1985-09-20 | Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav. |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0176875A3 (no) |
| JP (1) | JPS6185371A (no) |
| AU (1) | AU578739B2 (no) |
| DE (1) | DE3434948A1 (no) |
| FI (1) | FI853621L (no) |
| HU (1) | HU192363B (no) |
| IL (1) | IL76452A0 (no) |
| NO (1) | NO853694L (no) |
| ZA (1) | ZA857272B (no) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3434946A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | Diarylacetylene, ihre herstellung und verwendung |
| DE3434944A1 (de) * | 1984-09-22 | 1986-04-03 | Basf Ag, 6700 Ludwigshafen | L-substituierte tetralinderivate, ihre herstellung und verwendung |
| AU587994B2 (en) * | 1984-09-27 | 1989-09-07 | Processing Technologies International Limited | Low alcohol wine |
| US5030765A (en) * | 1986-05-23 | 1991-07-09 | Hoffmann-La Roche Inc. | Novel tetrahydronaphthalene and indane derivatives |
| 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 |
| AT388728B (de) * | 1987-03-17 | 1989-08-25 | Hoffmann La Roche | Neue tetrahydronaphthalin- und indanderivate |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK159967C (da) * | 1977-12-22 | 1991-06-03 | Hoffmann La Roche | Analogifremgangsmaade til fremstilling af terapeutisk aktive stilbenderivater |
| EP0084667B1 (de) * | 1982-01-23 | 1985-09-18 | BASF Aktiengesellschaft | Phenylethylen-Derivate, ihre Herstellung und Verwendung als Arzneimittel |
-
1984
- 1984-09-22 DE DE19843434948 patent/DE3434948A1/de not_active Withdrawn
-
1985
- 1985-09-19 EP EP85111834A patent/EP0176875A3/de not_active Withdrawn
- 1985-09-20 HU HU853547A patent/HU192363B/hu unknown
- 1985-09-20 FI FI853621A patent/FI853621L/fi not_active Application Discontinuation
- 1985-09-20 NO NO853694A patent/NO853694L/no unknown
- 1985-09-22 IL IL76452A patent/IL76452A0/xx unknown
- 1985-09-23 ZA ZA857272A patent/ZA857272B/xx unknown
- 1985-09-24 JP JP60209008A patent/JPS6185371A/ja active Pending
- 1985-09-24 AU AU47834/85A patent/AU578739B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| DE3434948A1 (de) | 1986-04-03 |
| FI853621A0 (fi) | 1985-09-20 |
| ZA857272B (en) | 1986-05-28 |
| HU192363B (en) | 1987-05-28 |
| AU4783485A (en) | 1986-03-27 |
| FI853621L (fi) | 1986-03-23 |
| JPS6185371A (ja) | 1986-04-30 |
| IL76452A0 (en) | 1986-01-31 |
| EP0176875A3 (de) | 1987-05-27 |
| AU578739B2 (en) | 1988-11-03 |
| HUT39434A (en) | 1986-09-29 |
| EP0176875A2 (de) | 1986-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI88025B (fi) | Foerfarande foer framstaellning av terapeutiskt aktiva vinylfenolderivat | |
| JPH0342252B2 (no) | ||
| EP0303186B1 (de) | Arylphosphorderivate, ihre Herstellung und Verwendung | |
| JP2556577B2 (ja) | 新規なスチルベン誘導体 | |
| US4539154A (en) | Polyene compounds | |
| FR2598706A1 (fr) | Derives de tetrahydronaphtalene, compositions pharmaceutiques les contenant et procede de preparation | |
| PT521471E (pt) | Derivados de pirimidina como inibidores da hmg-coa redutase | |
| JPS61502467A (ja) | メバロノラクトンのピラゾ−ル同族体およびその誘導体、それらの製造方法ならびに用途 | |
| DE3202100A1 (de) | Substituierte benzoesaeure-4-hydroxyanilide, ihre herstellung und diese enthaltende pharmazeutische zubereitungen | |
| CS235548B2 (en) | Method of tetrahydronaphthalene and indane new derivatives production | |
| US5112986A (en) | 1-benzyl-3-hydroxymethyl-indazole compounds and derivatives | |
| JP2006508930A (ja) | 新規生物活性ジフェニルエテン化合物およびその治療への適用 | |
| JPH01301661A (ja) | 新規ピリジル誘導体 | |
| NO853694L (no) | Vinyltetrazolylfenylderivater, fremstilling og anvendelse derav. | |
| JP2796876B2 (ja) | 置換ピロリジン化合物および医薬組成物 | |
| IE52630B1 (en) | Substituted biphenyl compounds | |
| US3953453A (en) | Trifluoromethyl substituted analogs of quinine and quinidine | |
| CA1161044A (en) | 5-amino-tetrazole derivatives of retinoic acids, their preparation and pharmaceutical formulations containing these derivatives | |
| JPH0512336B2 (no) | ||
| US6433021B1 (en) | Indane compounds and their pharmaceutical use | |
| US3567721A (en) | Indazolecarboxylic acids and derivatives thereof | |
| US4578522A (en) | Biaryl aldehyde | |
| US3985788A (en) | Phenyl propionic acids and derivatives thereof | |
| US3845215A (en) | Phenylalkane derivatives in the treatment of inflammation | |
| JPS5879944A (ja) | ３，５−ジ・タ−シヤリ−・ブチルスチレン誘導体及び抗炎症、鎮痛、解熱剤並びに血小板凝集阻害剤 |