DE19509697A1 - New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv. - Google Patents
New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv.Info
- Publication number
- DE19509697A1 DE19509697A1 DE19509697A DE19509697A DE19509697A1 DE 19509697 A1 DE19509697 A1 DE 19509697A1 DE 19509697 A DE19509697 A DE 19509697A DE 19509697 A DE19509697 A DE 19509697A DE 19509697 A1 DE19509697 A1 DE 19509697A1
- Authority
- DE
- Germany
- Prior art keywords
- group
- mmol
- alkyl
- groups
- general formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- -1 borneol ester Chemical class 0.000 title claims description 28
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 title abstract description 4
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 title abstract 2
- 229940116229 borneol Drugs 0.000 title abstract 2
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 title abstract 2
- RZARFIRJROUVLM-UHFFFAOYSA-N 3-azaniumyl-2-hydroxy-3-phenylpropanoate Chemical compound OC(=O)C(O)C(N)C1=CC=CC=C1 RZARFIRJROUVLM-UHFFFAOYSA-N 0.000 title 1
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 10
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 4
- 125000000466 oxiranyl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 150000001637 borneol derivatives Chemical class 0.000 claims description 9
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical group [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 2
- 101100294102 Caenorhabditis elegans nhr-2 gene Proteins 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 2
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 2
- 229960004853 betadex Drugs 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 2
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 2
- 150000003951 lactams Chemical class 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 125000002252 acyl group Chemical group 0.000 abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 3
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 abstract 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 238000000746 purification Methods 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- 239000012230 colorless oil Substances 0.000 description 12
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 12
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 102000004243 Tubulin Human genes 0.000 description 8
- 108090000704 Tubulin Proteins 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 102000029749 Microtubule Human genes 0.000 description 7
- 108091022875 Microtubule Proteins 0.000 description 7
- 229940123237 Taxane Drugs 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 210000004688 microtubule Anatomy 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 229940122803 Vinca alkaloid Drugs 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000006116 polymerization reaction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000004140 cleaning Methods 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000000394 mitotic effect Effects 0.000 description 4
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- 239000002574 poison Substances 0.000 description 4
- 231100000614 poison Toxicity 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- DTGKSKDOIYIVQL-KTOWXAHTSA-N (4r)-4,7,7-trimethylbicyclo[2.2.1]heptan-3-ol Chemical compound C1C[C@@]2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-KTOWXAHTSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
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- 229940063683 taxotere Drugs 0.000 description 3
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- 229960001278 teniposide Drugs 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
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- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
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- 238000009736 wetting Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Die Erfindung betrifft neue pharmakologisch wirksame Verbindungen, welche die Fähigkeit haben, die Tubulin-Polymerisation bzw. Tubulin-Depolymerisation zu beeinflussen.The invention relates to new pharmacologically active compounds which Have the ability to tubulin polymerization or tubulin depolymerization influence.
Eine Reihe natürlicher Mitosegifte werden als Antitumormittel eingesetzt bzw. befinden sich in der klinischen Prüfung. Es existieren verschiedene Klassen dieser Mitosegifte, die ihre zytotoxische Wirkung entweder durch Inhibition der Polymerisation von Mikrotubuli im Spindelapparat entfalten (z. B. Vinca-Alkaloide, Colchicin) oder dies durch eine GTP- unabhängige Steigerung der Polymerisation des Tubulins und Verhinderung der Depolymerisation von Mikrotubuli erreichen (z. B. Taxol, Taxotere). Mitosegifte haben aufgrund bisher unverstandener physikochemischer Eigenschaften und durch die Besonderheiten neoplastischer Zellen eine gewisse Selektivität für Tumorzellen, es besteht jedoch auch eine nicht unerhebliche Zytotoxizität gegenüber nicht transformierten Zellen.A number of natural mitotic poisons are used as antitumor agents themselves in the clinical trial. There are different classes of these mitotic poisons that their cytotoxic effects either by inhibiting the polymerization of microtubules unfold in the spindle apparatus (e.g. vinca alkaloids, colchicine) or this by a GTP independent increase in the polymerization of tubulin and prevention of Achieve depolymerization of microtubules (e.g. Taxol, Taxotere). Have mitotic poisons due to physicochemical properties not yet understood and by Special features of neoplastic cells are a certain selectivity for tumor cells, it however, there is also a not inconsiderable cytotoxicity towards transformed cells.
Vinca-Alkaloide besitzen bis heute große Bedeutung in der kombinierten Chemotherapie myeloischer Tumore. Taxane haben in jüngster Zeit bedeutende Anwendungsgebiete erschlossen, die durch bisher verfügbare Zytostatika nicht zugänglich waren, z. B. Ovarialkarzinome, maligne Melanome. Die Nebenwirkungen der Taxane sind allerdings denen anderer Zytostatika vergleichbar (z. B. Haarausfall, sensorische Neuropathie). Multi-Drug-resistente Tumorzellen, die das P-Glycoprotein überexprimieren sind gegenüber Taxanen resistent. Die begrenzte Verfügbarkeit des Naturstoffs Taxol behindert zudem eine breitere klinische Testung.Vinca alkaloids are still very important in combined chemotherapy myeloid tumors. Taxanes have recently had important areas of application tapped that were not accessible through previously available cytostatics, z. B. Ovarian cancer, malignant melanoma. The side effects of taxanes, however, are comparable to other cytostatics (e.g. hair loss, sensory neuropathy). Multi-drug resistant tumor cells that are overexpressing the P-glycoprotein resistant to taxanes. The limited availability of the natural product taxol also hinders broader clinical testing.
Es werden deshalb Naturstoffe und synthetische Pharmaka getestet, die ein von den bisherigen Mitosegiften abweichendes Wirkspektrum besitzen. Eine in vitro Versuchsanordnung ermöglicht die Suche nach Substanzen, die die GTP-abhängige Polymersiation von Tubulin nicht beeinflussen, die Depolymersiation der gebildeten Mikrotubuli jedoch verhindern. Substanzen mit einem solchen Wirkprofil sollten die vielseitigen Funktionen von Mikrotubuli in extranukleären Zellkompartimenten weniger stark beeinflussen, als die Dynamik des Spindelapparats während der Mitose (Meta- /Anaphase). Folgerichtig sollten solche Verbindungen geringere Nebenwirkungen in vivo zeigen als Taxane oder Vinca-Alkaloide.Therefore natural substances and synthetic pharmaceuticals are tested, which one of the previous mitosis poisons have a different spectrum of action. An in vitro Experimental setup enables the search for substances that are GTP-dependent Polymerization of tubulin does not affect the depolymerization of the formed However, prevent microtubules. Substances with such an activity profile should versatile functions of microtubules in extranuclear cell compartments less greatly affect the dynamics of the spindle apparatus during mitosis (meta- / Anaphase). Consequently, such compounds should have fewer side effects in vivo show as taxanes or vinca alkaloids.
Tubulin ist ein essentieller Bestandteil der mitotischen Spindel. Es dient unter anderem zur Aufrechterhaltung der Zellform, zum Transport von Organellen innerhalb der Zelle und zur Beeinflussung der Zellbeweglichkeit.Tubulin is an essential part of the mitotic spindle. It serves among other things to maintain the cell shape, to transport organelles within the cell and to influence cell mobility.
Taxane stellten bislang die einzige bekannte Strukturklasse dar, die in der Lage ist, die Polymerisation von Tubulin (überwiegend in der G2-Phase) zu beschleunigen sowie die gebildeten Mikrotubuli-Polymere zu stabilisieren. Dieser Mechanismus unterscheidet sich deutlich von denjenigen die andere, ebenfalls die phasenspezifische Zellteilung beeinflussende Strukturklassen aufweisen. So hemmen beispielsweise Substanzen aus der Gruppe der Vinca-Alkaloide (z. B. Vincristine und Vinblastine) aber auch Colchicin die Polymerisation der Tubulindimeren in der M-Phase.To date, taxanes have been the only known structural class that is able to Polymerization of tubulin (predominantly in the G2 phase) to accelerate as well stabilize formed microtubule polymers. This mechanism differs clearly the other, also the phase-specific cell division have influencing structure classes. For example, inhibit substances from the Group of vinca alkaloids (e.g. vincristine and vinblastine) but also colchicine Polymerization of the tubulin dimers in the M phase.
Es wird nun gefunden, daß vergleichsweise einfach herzustellende Verbindungen der Formel I in der Lage sind, die Depolymerisation von Mikrotubuli zu hemmen. Auf Grund dieser Eigenschaften stellen die Verbindungen der Formel I wertvolle Pharmaka dar, die prinzipiell in der Lage sind, die schwer zu synthetisierenden und in ausreichenden Mengen noch nicht verfügbaren Taxane wie z. B. Taxol und Taxotere® in der Therapie maligner Tumore zu ergänzen bzw. zu ersetzen (EP-A 253739).It is now found that the connections of the Formula I are able to inhibit the depolymerization of microtubules. Because of of these properties, the compounds of formula I are valuable pharmaceuticals which are in principle able to process those that are difficult to synthesize and sufficient Amounts of not yet available taxanes such as B. Taxol and Taxotere® in therapy to supplement or replace malignant tumors (EP-A 253739).
Die neuen Borneolderivate sind gekennzeichnet durch die allgemeine Formel IThe new borneol derivatives are characterized by the general formula I
worin
R¹ einen gegebenenfalls durch Halogenatome, C₁-C₄-Alkylgruppen, C₁-C₄-
Alkoxygruppen, C₁-C₆-Alkoxycarbonylgruppen oder C₁-C₈-
Acyloxygruppen substituierter Phenylrest darstellt,
R² ein Wasserstoffatom, eine C₁-C₄-Alkylgruppe, substituiertes Aryl, eine C₁-
C₆-Alkoxycarbonylgruppe oder eine C₁-C₈-Acylgruppe symbolisiert,
R³ ein Wasserstoffatom, eine C₁-C₄-Alkylgruppe, eine C₁-C₄-Acylgruppe oder
eine Tri-C₁-C₄-alkylsilylgruppe bedeutet und worin
R⁴ und R⁷ ein Wasserstoffatom, einen C₁-C₄-Alkylrest oder einen gegebenenfalls durch
Halogenatome, C₁-C₄-Alkylgruppe, C₁-C₉-Alkoxygruppen, C₁-C₄-
Alkoxycarbonylgruppen oder C₁-C₈-Acyloxygruppen substituierter
Phenylrest bedeuten und
R⁵ und R⁶ ein Wasserstoffatom, eine Hydroxygruppe, oder eine C₁-C₈-Acyloxygruppe
darstellen oder gemeinsam eine Kohlenstoff-Kohlenstoffbindung oder ein
Sauerstoffatom symbolisieren oder
R⁴ und R⁵ und /oder R⁶ und R⁷ jeweils gemeinsam eine Carbonylgruppe, eine C₁-C₄-
Alkylidengruppe oder gewünschtenfalls durch eine C₁-C₃-Alkylgruppe
substituierte Oxirangruppe bedeuten,
sowie gegebenenfalls deren Salze mit physiologisch verträglichen Säuren, sowie deren α-,
β- oder γ-Cyclodextrinclathrate und die in Liposomen verkapselten Verbindungen der
allgemeinen Formel I bedeuten.
wherein
R¹ represents a phenyl radical optionally substituted by halogen atoms, C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups, C₁-C₆ alkoxycarbonyl groups or C₁-C₈ acyloxy groups,
R² symbolizes a hydrogen atom, a C₁-C₄-alkyl group, substituted aryl, a C₁-C₆-alkoxycarbonyl group or a C₁-C₈-acyl group,
R³ represents a hydrogen atom, a C₁-C₄-alkyl group, a C₁-C₄-acyl group or a tri-C₁-C₄-alkylsilyl group and wherein
R⁴ and R⁷ represent a hydrogen atom, a C₁-C₄ alkyl radical or a phenyl radical which is optionally substituted by halogen atoms, C₁-C₄ alkyl group, C₁-C₉ alkoxy groups, C₁-C₄ alkoxycarbonyl groups or C₁-C₈ acyloxy groups and
R⁵ and R⁶ represent a hydrogen atom, a hydroxy group, or a C₁-C₈ acyloxy group or together symbolize a carbon-carbon bond or an oxygen atom or
R⁴ and R⁵ and / or R⁶ and R⁷ each together represent a carbonyl group, a C₁-C₄ alkylidene group or, if desired, an oxirane group substituted by a C₁-C₃ alkyl group,
and optionally their salts with physiologically compatible acids, and their α-, β- or γ-cyclodextrin clathrates and the compounds of the general formula I encapsulated in liposomes.
Die Erfindung betrifft die Diastereomeren und/oder Enantiomeren dieser Borneolderivate und auch deren Gemische.The invention relates to the diastereomers and / or enantiomers of these borneol derivatives and also their mixtures.
Als Alkylgruppen dieser Borneolderivate sind gerad- oder verzweigtkettige Gruppen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.- Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl.Straight or branched chain groups are possible as alkyl groups of these borneol derivatives consider, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.- Butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
Als Arylrest dieser Verbindungen kommen alicyclische, carbocyclische oder heterocyclische Reste wie z. B. Phenyl, Naphtyl, Furyl, Thienyl, Pyridyl, Pyrazolyl, Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, die üblicherweise einfach oder mehrfach substituiert sein können, in Frage.The aryl radical of these compounds are alicyclic, carbocyclic or heterocyclic radicals such as. B. phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, Pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, which are usually simple or can be substituted several times in question.
Solche Substituenten sind beispielsweise Alkoxy-, Acyl- sowie Acyloxygruppen, wobei Methoxy-, Ethoxy- Propoxy- thaltenlsopropoxy-, t-Butyloxy-, Formyl, Acetyl, Propionyl-. und Isopropionylgruppen bevorzugt sind.Such substituents are, for example, alkoxy, acyl and acyloxy groups, where Methoxy-, ethoxy- propoxy- thaltenlsopropoxy-, t-butyloxy-, formyl, acetyl, Propionyl. and isopropionyl groups are preferred.
Freie Hydroxygruppen können funktionell abgewandelt sein, beispielsweise durch Veretherung oder Veresterung, wobei freie Hydroxygruppen bevorzugt sind.Free hydroxyl groups can be functionally modified, for example by Etherification or esterification, free hydroxyl groups being preferred.
Als Ether- und Acylreste kommen die dem Fachmann bekannten Reste in Betracht. Bevorzugt sind leicht abspaltbare Etherreste, wie beispielsweise der Tetrahydropyranyl-, Tetrahydrofuranyl-, tert.-Butyldimethylsilyl-, tert.-Butyldiphenylsilyl-, Tribenzylsilylrest. Als Acylreste kommen z. B. Acetyl, Propionyl, Butyryl, Benzoyl in Frage.The radicals known to the person skilled in the art are suitable as ether and acyl radicals. Easily removable ether residues, such as, for example, tetrahydropyranyl, Tetrahydrofuranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl radical. As acyl residues come e.g. B. acetyl, propionyl, butyryl, benzoyl in question.
Halogen in den Definitionen für X bedeutet Fluor, Chlor, Brom und Iod.Halogen in the definitions for X means fluorine, chlorine, bromine and iodine.
Zur Salzbildung mit den freien Basen sind anorganische und organische Säuren geeignet, wie sie dem Fachmann zur Bildung physiologisch verträglicher Salze bekannt sind.Inorganic and organic acids are suitable for salt formation with the free bases, as are known to the person skilled in the art for the formation of physiologically compatible salts.
Die Erfindung betrifft ferner Verfahren zur Herstellung von Borneolderivaten der Formel I, welches dadurch gekennzeichnet, daß man einen Alkohol der allgemeinen Formel IIThe invention further relates to processes for the preparation of borneol derivatives of the formula I, which is characterized in that an alcohol of the general formula II
in der R⁴, R⁵, R⁶ und R⁷ die oben genannten Bedeutungen haben und in R⁵ oder R⁶ enthaltene Hydroxylgruppen gegebenenfalls geschützt sind, mit einem Lactam der allgemeinen Formel IIIa oder einer Carboxylverbindung der allgemeinen Formel IIIb,in which R⁴, R⁵, R⁶ and R⁷ have the meanings given above and in R⁵ or R⁶ contained hydroxyl groups are optionally protected with a lactam general formula IIIa or a carboxyl compound of general formula IIIb,
mit R¹, R² und R³ in der oben genannten Bedeutung und X′ in der Bedeutung OH, O- C(O)-CH(OR²)-CH(NHR²)-R¹, Halogen oder C₁-C₁₀-Alkyl haben kann und in IIIa bzw. IIIb enthaltenen Hydroxylgruppen gegebenenfalls geschützt sind, verestert, gegebenenfalls vorhandene Doppelbindungen oxidiert, geschützte Hydroxylgruppen freisetzt und in ein Derivat der allgemeinen Formel I überführt.with R¹, R² and R³ in the abovementioned meaning and X ′ in the meaning OH, O- C (O) -CH (OR²) -CH (NHR²) -R¹, halogen or C₁-C₁₀-alkyl can have and in IIIa or IIIb-containing hydroxyl groups are optionally protected, esterified, any double bonds present are oxidized, protected hydroxyl groups releases and converted into a derivative of general formula I.
Zur Veresterung der Alkoholfunktion wird mit einer Base wie z. B. Metallhydriden (z. B. Natriumhydrid), Alkalialkoholaten (z. B. Natriummethanolat, Kalium-tert.-butanolat), Alkalihexamethyldisilazan (z. B. Natriumhexamethyldisilazan), 1,5- Diazabicyclo[4.3.0]non-5-en (DBN), 1,8-Diazabicyclo[5.4.0]undec-7-en (DBU), Triethylamin, 4(Dimethylamino)pyridin (DMAP), 1,4-Diazabicyclo[2.2.2]octan (DABCO) deprotoniert und mit Verbindungen der allgemeinen Formeln IIIa oder IIIb oder mit anderen geeigneten Carbonsäurederivaten wie z. B. Säureamiden, Säureanhydriden in einem inerten Solvens wie z. B. Dichlormethan, Diethylether, Tetrahydrofuran bei -70°C bis +50°C umgesetzt. Bevorzugt wird die Umsetzung mit Natriumhexamethyldisilazan als Base, einem cyclischen Säureamid als Carbonsäurederivat, Tetrahydrofuran als Solvens bei Temperaturen von -40°C bis +25°C.To esterify the alcohol function with a base such as. B. metal hydrides (e.g. Sodium hydride), alkali alcoholates (e.g. sodium methoxide, potassium tert-butoxide), Alkali hexamethyldisilazane (e.g. sodium hexamethyldisilazane), 1.5- Diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), Triethylamine, 4 (dimethylamino) pyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO) deprotonated and with compounds of the general formulas IIIa or IIIb or with other suitable carboxylic acid derivatives such as. B. acid amides, Acid anhydrides in an inert solvent such as e.g. B. dichloromethane, diethyl ether, Tetrahydrofuran implemented at -70 ° C to + 50 ° C. The reaction with is preferred Sodium hexamethyldisilazane as base, a cyclic acid amide as Carboxylic acid derivative, tetrahydrofuran as a solvent at temperatures from -40 ° C to + 25 ° C.
Falls R⁵ und R⁶ gemeinsam eine Bindung darstellen oder R⁴ und R⁵ und/oder R⁶ und R⁷ gemeinsam eine Alkylidengruppe darstellen, kann die Funktionalisierung der olefinischen Doppelbindung nach den, dem Fachmann bekannten Methoden erfolgen. Beispielsweise kann Wasserstoff angelagert werden z. B. durch kat. Hydrierung, es können Hydroxylgruppen eingeführt werden durch Wasseranlagerung (Hydroborierung, Oxymercurierung) oder durch 1.2-Bishydroxylierung z. B. mit Osmiumtetroxid oder Kaliumpermanganat.If R⁵ and R⁶ together represent a bond or R⁴ and R⁵ and / or R⁶ and R⁷ together represent an alkylidene group, the functionalization of the olefinic Double bond by the methods known to those skilled in the art. For example can hydrogen be added e.g. B. by cat. Hydrogenation, it can Hydroxyl groups are introduced by water addition (hydroboration, Oxymercurierung) or by 1.2-Bishydroxylierung z. B. with osmium tetroxide or Potassium permanganate.
Die Einführung einer Carbonylgruppe gelingt zum Beispiel durch Oxidation einer Hydroxylgruppe. Eine derartig erzeugte Carbonylgruppe kann beispielsweise reduziert, alkyliert oder als Carbonylkomponente in einer Wittig-Reaktion zum Aufbau modifizierter =CHR⁶-Gruppen verwendet werden.A carbonyl group can be introduced, for example, by oxidation of one Hydroxyl group. A carbonyl group produced in this way can be reduced, for example, alkylated or as a carbonyl component in a Wittig reaction for assembly modified = CHR⁶ groups can be used.
Falls R⁴ und R⁵ und/oder R⁶ und R⁷ gemeinsam eine gegebenenfalls substituierte Oxirangruppe darstellen, kann das Epoxid durch Nucleophile wie beispielsweise Wasser oder Carbonsäurederivate (Carbonsäuren, Carbonsäurehalogenide, Carbonsäure anhydride), in Gegenwart von mineralischen oder organischen Säuren wie beispielsweise Chlorwasserstoff, para-Toluolsulfonsäure oder Lewissäuren wie beispielsweise Bortrifluoridetherat, Titantetraisopropoxid, Cerammoniumnitrat entweder in inerten oder als Nucleophil fungierenden Lösungsmitteln bei -70°C bis +50°C gespalten werden. If R⁴ and R⁵ and / or R⁶ and R⁷ together an optionally substituted Oxirane group, the epoxy can by nucleophiles such as water or carboxylic acid derivatives (carboxylic acids, carboxylic acid halides, carboxylic acid anhydrides), in the presence of mineral or organic acids such as Hydrogen chloride, para-toluenesulfonic acid or Lewis acids such as, for example Boron trifluoride etherate, titanium tetraisopropoxide, cerium ammonium nitrate either in inert or solvents that act as nucleophiles are split at -70 ° C to + 50 ° C.
Biologische Wirkungen und Anwendungsbereiche der neuen Borneolderivate:
Die neuen Borneolderivate der Formel I sind wertvolle Pharmaka. Sie interagieren mit
Tubulin, indem sie gebildete Mikrotubuli stabilisieren und sind somit in der Lage, die
Zellteilung phasenspezifisch zu beeinflussen. Dies betrifft vor allem schnell wachsende,
neoplastische Zellen, deren Wachstum durch interzelluläre Regelmechnismen weitgehend
unbeeinflußt ist. Wirkstoffe dieser Art sind prinzipiell geeignet zur Behandlung von
Erkrankungen, bei denen die Beeinflussung der Zellteilung therapeutisch indiziert sein
kann wie dies z. B. bei der Therapie des morbus Alzheimer, der Malaria, der Therapie
von Erkrankungen, welche durch gram-negative Bakterien verursacht sind, sowie zur
Behandlung maligner Tumoren der Fall ist. Als Anwendungsbereich für maligne
Tumoren seien beispielweise genannt die Therapie von Ovarial-, Magen-, Colon-,
Adeno-, Brust-, Lungen-, Kopf- und Nacken-Karzinomen, dem malignen Melanom, der
akuten lymphozytären und myelocytären Leukämie. Die erfindungsgemäßen
Verbindungen können alleine oder zur Erzielung additiver oder synergistischer
Wirkungen in Kombination mit weiteren in der Tumortherapie anwendbaren Prinzipien
und Substanzklassen verwendet werden.Biological effects and areas of application of the new borneol derivatives:
The new borneol derivatives of formula I are valuable pharmaceuticals. They interact with tubulin by stabilizing formed microtubules and are therefore able to influence cell division in a phase-specific manner. This concerns above all fast growing, neoplastic cells, the growth of which is largely unaffected by intercellular control mechanisms. In principle, active substances of this type are suitable for the treatment of diseases in which the influencing of cell division can be therapeutically indicated, as is the case for B. in the treatment of Alzheimer's disease, malaria, the therapy of diseases caused by gram-negative bacteria, and for the treatment of malignant tumors. Examples of applications for malignant tumors include the therapy of ovarian, stomach, colon, adeno, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia. The compounds according to the invention can be used alone or to achieve additive or synergistic effects in combination with other principles and substance classes which can be used in tumor therapy.
Als Beispiele seien genannt die Kombination mitExamples include the combination with
- - Platinkomplexen wie z. B. Cisplatin, Carboplatin,- Platinum complexes such as B. cisplatin, carboplatin,
- - interkalierenden Substanzen z. B. aus der Klasse der Anthracycline wie z. B. Doxorubicin oder aus der Klasse der Antrapyrazole wie z. B. CI-941,- Intercalating substances e.g. B. from the class of anthracyclines such. B. Doxorubicin or from the class of antrapyrazoles such. B. CI-941,
- - mit Tubulin interagierenden Substanzen z. B. aus der Klasse der Vinca-Alkaloide wie z. B. Vincristin, Vinblastin oder aus der Klasse der Taxane wie z. B. Taxol, Taxotere oder aus der Klasse der Makrolide wie z. B. Rhizoxin oder andere Verbindungen wie z. B. Colchicin, Combretastatin A-4,- substances interacting with tubulin z. B. from the class of Vinca alkaloids such as B. vincristine, vinblastine or from the class of taxanes such. B. Taxol, Taxotere or from the class of macrolides such. B. rhizoxin or others Connections such as B. colchicine, combretastatin A-4,
- - DNA Topoisomeraseinhibitoren wie z. B. Camptothecin, Etoposid, Topotecan, Teniposid,- DNA topoisomerase inhibitors such as B. camptothecin, etoposide, topotecan, Teniposide,
- - Folat- oder Pyrimidin-Antimetaboliten wie z. B. Lometrexol, Gemcitubin,- Folate or pyrimidine antimetabolites such as B. lometrexol, gemcitubin,
- - DNA alkylierenden Verbindungen wie z. B. Adozelesin, Dystamycin A,- DNA alkylating compounds such. B. adozelesin, dystamycin A,
- - Inhibitoren von Wachstumsfaktoren (z. B. von PDGF, EGF, TGFβ, EGF) wie z. B. Somatostatin, Suramin, Bombesin-Antagonisten,- Inhibitors of growth factors (e.g. PDGF, EGF, TGFβ, EGF) such as e.g. B. Somatostatin, suramin, bombesin antagonists,
- - Inhibitoren der Protein Tyrosin Kinase oder der Protein Kinasen A oder C wie z. B. Erbstatin, Genistein, Staurosporin, Ilmofosin, 8-Cl-cAMP,- Inhibitors of protein tyrosine kinase or protein kinases A or C such as. B. Erbstatin, Genistein, Staurosporin, Ilmofosin, 8-Cl-cAMP,
- - Antihormonen aus der Klasse der Antigestagene wie z. B. Mifepriston, Onapriston oder aus der Klasse der Antiöstrogene wie z. B. Tamoxifen oder aus der Klasse der Antiandrogene wie z. B. Cyproteronacetat,- Anti-hormones from the class of anti-gestagens such. B. Mifepristone, Onapristone or from the class of anti-estrogens such. B. Tamoxifen or from the class of Antiandrogens such as B. cyproterone acetate,
- - Metastasen inhibierenden Verbindungen z. B. aus der Klasse der Eicosanoide wie z. B. PGI₂, PGE₁, 6-Oxo-PGE₁ sowie deren stabiler Derivate (z. B. Iloprost, Cicaprost, Beraprost), - Metastasis inhibiting compounds z. B. from the class of eicosanoids such as e.g. B. PGI₂, PGE₁, 6-oxo-PGE₁ and their stable derivatives (z. B. Iloprost, Cicaprost, beraprost),
- - Inhibitoren des transmembranären Ca2+-Influx wie z. B. Verapamil, Galopamil, Flunarizin, Diltiazem, Nifedipin, Nimodipin,- Inhibitors of the transmembrane Ca 2+ influx such. B. verapamil, galopamil, flunarizine, diltiazem, nifedipine, nimodipine,
- - Neuroleptika wie z. B. Chlorpromazin, Trifuoperazin, Thioridazin, Perphenazin,- Neuroleptics such as B. chlorpromazine, trifuoperazine, thioridazine, perphenazine,
- - Lokalanästhetika wie z. B. Carbanilat-Ca7, Cinchocain, Carbanilat-Ca3, Articain, Carbanilat, Lidocain.- Local anesthetics such as B. carbanilate-Ca7, cinchocaine, carbanilate-Ca3, articaine, Carbanilate, lidocaine.
- - die Angiogenese inhibierenden Substanzen wie z. B. anti-VEGF-Antikörpern, Endostatin B, Interferon α, AGM 1470,- The angiogenesis inhibiting substances such. B. anti-VEGF antibodies, Endostatin B, interferon α, AGM 1470,
- - Inhibitoren der Zellproliferation bei Psoriasis, Kaposisarcom, Neuroblastom.- Inhibitors of cell proliferation in psoriasis, kaposisarcom, neuroblastoma.
Die Erfindung betrifft auch Arzneimittel auf Basis der pharmazeutisch verträglichen, d. h. in den verwendeten Dosen nicht toxischen Borneolderivate der allgemeinen Formel I, gegebenenfalls zusammen mit den üblichen Hilfs- und Trägerstoffen.The invention also relates to pharmaceuticals based on the pharmaceutically acceptable, ie. H. in the doses used, non-toxic borneol derivatives of the general formula I, optionally together with the usual auxiliaries and carriers.
Die erfindungsgemäßen Verbindungen können nach an sich bekannten Methoden der Galenik zu pharmazeutischen Präparaten für die enterale, percutane, parenterale oder lokale Applikation verarbeitet werden. Sie können in Form von Tabletten, Dragees, Gel kapseln, Granulaten, Suppositorien, Implantaten, injizierbaren sterilen wäßrigen oder öligen Lösungen, Suspensionen oder Emulsionen, Salben, Cremes und Gelen verabreicht werden.The compounds of the invention can according to known methods of Galenics for pharmaceutical preparations for enteral, percutaneous, parenteral or local application are processed. They can be in the form of tablets, coated tablets, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels will.
Der oder die Wirkstoffe können dabei mit den in der Galenik üblichen Hilfsstoffen wie z. B. Gummiarabikum, Talk, Stärke, Mannit, Methylcellulose, Laktose, Tensiden wie Tweens oder Myrj, Magnesiumstearat, wäßrigen oder nicht wäßrigen Trägern, Paraffin derivaten, Netz-, Dispergier-, Emulgier-, Konservierungsmitteln und Aromastoffen zur Geschmackskorrektur (z. B. etherischen Ölen) gemischt werden.The active ingredient (s) can be combined with the auxiliaries customary in galenics such as e.g. B. gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as Tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting, dispersing, emulsifying, preserving and flavoring agents for Flavor correction (e.g. essential oils) can be mixed.
Die Erfindung betrifft somit auch pharmazeutische Zusammensetzungen, die als Wirk stoff zumindest eine erfindungsgemäße Verbindung enthalten. Eine Dosiseinheit enthält etwa 0,1-100 mg Wirkstoff(e). Die Dosierung der erfindungsgemäßen Verbindungen liegt beim Menschen bei etwa 0,1-1000 mg pro Tag.The invention thus also relates to pharmaceutical compositions which act as contain substance at least one compound of the invention. Contains one dose unit about 0.1-100 mg of active ingredient (s). The dosage of the compounds according to the invention in humans is around 0.1-1000 mg per day.
Die nachfolgenden Ausführungsbeispiele dienen zur weiteren Erläuterung des erfindungsgemäßen Verfahrens.The following exemplary embodiments serve to explain the inventive method.
Unter Argonatmosphäre werden 42 mg (0,071 mmol) des nach Beispiel 1a dargestellten
Silylethers in 3 ml wasserfreiem Tetrahydrofuran über Molsieb (3 Å) vorgelegt und bei
23°C mit 71 µl (0,071 mmol) einer 1 M Lösung von Tetrabutylammoniumfluorid in
Tetrahydrofuran versetzt. Nach 20 min Rühren bei 23°C war das Edukt vollständig
abreagiert (DC-Kontrolle; Methyl-t-butylether/Petrolether 1 : 1; Rf = 0,45), und die
Reaktion wird mit gesättigter Ammoniumchlorid-Lösung versetzt. Es wird fünfmal mit
Methyl-t-butylether ausgeschüttelt, über Magnesiumsulfat getrocknet und das
Lösungsmittel im Vakuum abdestilliert. Die Reinigung erfolgt flash-chromatographisch
(Methyl-t-butylether/Petrolether 1 : 4, Rf = 0,24). Isoliert werden 10 mg (0,023 mmol,
33%) der Titelverbindung als gelbliches Öl.
¹H-NMR (400 MHz, CDCl₃): δ = 7,25-7,38 (5H), 5,41 (1H), 5,18 (1H), 5,05 (1H), 4,83
(1H), 4,69 (1H), 4,49 (1H), 3,16 (1H), 2,56 (1H), 2,48 (1H), 2,19 (1H), 2,01 (1H), 1,40
(9H), 1,26 (1H), 0,94 (3H), 0,90 (3H), 0,88 (3H) ppm.Under an argon atmosphere, 42 mg (0.071 mmol) of the silyl ether prepared according to Example 1a in 3 ml of anhydrous tetrahydrofuran are introduced through molecular sieve (3 Å) and 71 μl (0.071 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added at 23 ° C. After stirring for 20 min at 23 ° C., the starting material had reacted completely (TLC control; methyl t-butyl ether / petroleum ether 1: 1; R f = 0.45), and saturated ammonium chloride solution is added to the reaction. It is extracted five times with methyl t-butyl ether, dried over magnesium sulfate and the solvent is distilled off in vacuo. The purification is carried out by flash chromatography (methyl t-butyl ether / petroleum ether 1: 4, R f = 0.24). 10 mg (0.023 mmol, 33%) of the title compound are isolated as a yellowish oil.
1 H-NMR (400 MHz, CDCl₃): δ = 7.25-7.38 (5H), 5.41 (1H), 5.18 (1H), 5.05 (1H), 4.83 (1H) , 4.69 (1H), 4.49 (1H), 3.16 (1H), 2.56 (1H), 2.48 (1H), 2.19 (1H), 2.01 (1H), 1.40 (9H), 1.26 (1H), 0.94 (3H), 0.90 (3H), 0.88 (3H) ppm.
Es werden 33 mg (0,2 mmol) des nach Beispiel 1b dargestellten Alkohols in 3 ml
wasserfreiem Tetrahydrofuran unter Argon vorgelegt und 100,7 mg (0,24 mmol)
(3R,4S)-1-[(1,1-dimethylethoxy)carbonyl]-3-triisopropylsilyloxy-4-ph-enyl-2-azetidinon
im Argongegenstrom dazugegeben. Zu der auf -35°C abgekühlten Lösung werden 0,44
ml (0,44 mmol) einer 1 M Natriumbis(trimethylsilyl)amid-Lösung in Tetrahydrofuran
gegeben. Nach dreistündigem Rühren bei -30°C (DC-Kontrolle, Methyl-t-
butylether/Petrolether 1 : 4; Rf = 0.62) erfolgt der Abbruch der Reaktion durch Zugabe
von gesättigter Ammoniumchlorid-Lösung. Anschließend wird viermal mit Methyl-t-
butylether extrahiert, über Magnesiumsulfat getrocknet, das Lösungsmittel am
Rotationsverdampfer abdestiliert und das Rohprodukt flach chromatographisch gereinigt.
Isoliert werden 69 mg (0.12 mmol; 60%) der Titelverbindung als farbloses Öl
¹H-NMR (400MHz, CDCl₃): δ=7,20-7,34 (5H), 5,59 (1H), 5,07 (1H), 5,01 (1H), 4,81
(1H), 4,63 (1H), 4,61 (1H), 2,57 (1H), 2,44 (1H), 2,17 (1H), 1,96 (1H), 1,40 (9H), 1,10
(1H), 0,94 (21H), 0,90 (1H), 0,88 (1H), 0,86 (1H) ppm.
33 mg (0.2 mmol) of the alcohol shown in Example 1b are placed in 3 ml of anhydrous tetrahydrofuran under argon and 100.7 mg (0.24 mmol) (3R, 4S) -1 - [(1,1-dimethylethoxy ) carbonyl] -3-triisopropylsilyloxy-4-ph-enyl-2-azetidinone added in an argon countercurrent. 0.44 ml (0.44 mmol) of a 1 M sodium bis (trimethylsilyl) amide solution in tetrahydrofuran are added to the solution, which has cooled to -35 ° C. After stirring for three hours at -30 ° C (TLC control, methyl t-butyl ether / petroleum ether 1: 4; R f = 0.62), the reaction is terminated by adding saturated ammonium chloride solution. The mixture is then extracted four times with methyl t-butyl ether, dried over magnesium sulfate, the solvent is distilled off on a rotary evaporator and the crude product is purified by flat chromatography. 69 mg (0.12 mmol; 60%) of the title compound are isolated as a colorless oil
1 H-NMR (400MHz, CDCl₃): δ = 7.20-7.34 (5H), 5.59 (1H), 5.07 (1H), 5.01 (1H), 4.81 (1H), 4.63 (1H), 4.61 (1H), 2.57 (1H), 2.44 (1H), 2.17 (1H), 1.96 (1H), 1.40 (9H), 1 , 10 (1H), 0.94 (21H), 0.90 (1H), 0.88 (1H), 0.86 (1H) ppm.
Unter einer Argonatmosphäre werden 852 mg (13,08 mmol) Zinkstaub und 0,5 ml (0,03
mmol) Dibrommethan in 5 ml wasserfreiem Tetrahydrofuran vorgelegt. Bei
Raumtemperatur tropft man eine Lösung von 1 mol/l Titantetrachlorid in Dichlormethan
dazu. Es bildet sich eine dunkelbraune Lösung, zu der nach 20 Minuten 280 mg (1,3
mmol) des nach Beispiel 1c dargestellten Ketons, gelöst in 3 ml wasserfreiem
Tetrahydrofuran, über einen Zeitraum von 15 Minuten zugetropft wird. Anschließend
wird 21 Stunden bei 23°C gerührt. Zur Aufarbeitung wird mit 15 ml Methyl-t-butylether
verdünnt, auf 5%ige HCL gegeben und die wäßrige Phase fünfmal mit Methyl-t-
butylether ausgeschüttelt. Die vereinigten organischen Phasen werden mit gesättigter
Natriumchlorid-Lösung gewaschen und das Lösungsmittel im Vakuum abdestilliert. Die
Reinigung erfolgt flash-chromatographisch (Methyl-t-butylether/Petrolether 1 : 4; Rf =
0,23). Isoliert werden 48 mg (0,29 mmol, 22%) der Titelverbindung als farbloses Öl
¹H-NMR (400 MHz, CDCl₃): δ = 4,80 (1H), 4,61 (1H), 4,07 (1H), 2,55 (1H), 2,43
(1H), 2,13 (1H), 1,91 (1H), 1,10 (1H), 0,89 (3H), 0,87 (3H), 0,85 (3H) ppm.852 mg (13.08 mmol) of zinc dust and 0.5 ml (0.03 mmol) of dibromomethane in 5 ml of anhydrous tetrahydrofuran are placed in an argon atmosphere. A solution of 1 mol / l titanium tetrachloride in dichloromethane is added dropwise at room temperature. A dark brown solution is formed, to which, after 20 minutes, 280 mg (1.3 mmol) of the ketone shown in Example 1c, dissolved in 3 ml of anhydrous tetrahydrofuran, are added dropwise over a period of 15 minutes. The mixture is then stirred at 23 ° C for 21 hours. For working up, it is diluted with 15 ml of methyl t-butyl ether, added to 5% HCl and the aqueous phase is shaken out five times with methyl t-butyl ether. The combined organic phases are washed with saturated sodium chloride solution and the solvent is distilled off in vacuo. The purification is carried out by flash chromatography (methyl t-butyl ether / petroleum ether 1: 4; R f = 0.23). 48 mg (0.29 mmol, 22%) of the title compound are isolated as a colorless oil
1 H-NMR (400 MHz, CDCl₃): δ = 4.80 (1H), 4.61 (1H), 4.07 (1H), 2.55 (1H), 2.43 (1H), 2.13 (1H), 1.91 (1H), 1.10 (1H), 0.89 (3H), 0.87 (3H), 0.85 (3H) ppm.
Zu einer eisgekühlten Lösung von 4,85g (24,7 mmol) des nach Beispiel 1d dargestellten
Acetates in 20 ml Eisessig und 9 ml Acetanhydrid werden 7,0g (70 mmol) CrO₃ in 11 ml
Acetanhydrid über einen Zeitraum von zwei Stunden getropft. Anschließend wird das
Reaktionsgemisch auf Raumtemperatur erwärmt und sechs Tage bei dieser Temperatur
gerührt. Der Reaktionsverlauf wird mittels DC-Kontrolle verfolgt (Methyl-t-
butylether/Petrolether 1 : 4; Rf =0,47). Der Reaktionsansatz wird auf ca. 0,5 l Wasser
gegeben und fünfmal mit Methyl-t-butylether extrahiert. Zur Phasentrennung wird über
Celite filtriert. Die vereinigten organischen Phasen werden mit gesättigter Na₂CO₃-
Lösung gewaschen und über Magnesiumsulfat getrocknet. Nach Abdestillieren des
Lösungsmittels im Vakuum erfolgt die Reinigung des Rohproduktes flash-
chromatographisch (Methyl-t-butylether/Petrolether 1 : 9, Rf = 0,07). Isoliert werden
1,894g (9,0 mmol; 36%) der Titelverbindung als farblose Kristalle.
¹H-NMR (400 MHz, CDCl₃): δ = 5,07 (1H), 2,63 (1H), 2,55 (1H), 2,19 (1H), 2,07 (3H),
2,00 (1H), 1,32 (1H), 1,03 (3H), 1,01 (3H), 0,95 (3H) ppm.To an ice-cooled solution of 4.85 g (24.7 mmol) of the acetate shown in Example 1d in 20 ml of glacial acetic acid and 9 ml of acetic anhydride, 7.0 g (70 mmol) of CrO₃ in 11 ml of acetic anhydride are added dropwise over a period of two hours. The reaction mixture is then warmed to room temperature and stirred at this temperature for six days. The course of the reaction is monitored by TLC control (methyl t-butyl ether / petroleum ether 1: 4; R f = 0.47). The reaction mixture is poured into about 0.5 l of water and extracted five times with methyl t-butyl ether. To separate the phases, filter through Celite. The combined organic phases are washed with saturated Na₂CO₃ solution and dried over magnesium sulfate. After the solvent has been distilled off in vacuo, the crude product is purified by flash chromatography (methyl t-butyl ether / petroleum ether 1: 9, R f = 0.07). 1,894 g (9.0 mmol; 36%) of the title compound are isolated as colorless crystals.
1 H-NMR (400 MHz, CDCl₃): δ = 5.07 (1H), 2.63 (1H), 2.55 (1H), 2.19 (1H), 2.07 (3H), 2.00 (1H), 1.32 (1H), 1.03 (3H), 1.01 (3H), 0.95 (3H) ppm.
2,991g (19 mmol) (1R)-(+)-Borneol werden in 3,5g (34 mmol) Essigsäureanhydrid und
7 ml Pyridin auf 100°C erhitzt und 11 Stunden bei dieser Temperatur gerührt.
Anschließend wird das Reaktionsgemisch abgekühlt und auf Wasser gegeben. Es wird
dreimal mit Methyl-t-butylether ausgeschüttelt und die vereinigten organischen Phasen
werden mit gesättigter Ammoniumchlorid-Lösung gewaschen. Nach dem Trocknen über
Magnesiumsulfat wird das Lösungsmittel im Vakuum abdestilliert. Isoliert werden 3.3g
(17mmol; 89%) der Titelverbindung als farbloses Öl, das man ohne Reinigung weiter
umsetzt.
¹H-NMR (400 MHz, CDCl₃): δ = 4,87 (1H), 2,35 (1H), 2,06 (3H), 1,93 (1H), 1,74 (1H),
1,67 (1H), 1,19-1,34 (2H), 0,96 (1H), 0,90 (3H), 0,87 (3H), 0,83 (3H) ppm.2.991 g (19 mmol) (1R) - (+) - borneol are heated to 100 ° C. in 3.5 g (34 mmol) acetic anhydride and 7 ml pyridine and stirred at this temperature for 11 hours.
The reaction mixture is then cooled and poured onto water. It is extracted three times with methyl t-butyl ether and the combined organic phases are washed with saturated ammonium chloride solution. After drying over magnesium sulfate, the solvent is distilled off in vacuo. 3.3 g (17 mmol; 89%) of the title compound are isolated as a colorless oil which can be reacted further without purification.
1 H-NMR (400 MHz, CDCl₃): δ = 4.87 (1H), 2.35 (1H), 2.06 (3H), 1.93 (1H), 1.74 (1H), 1.67 (1H), 1.19-1.34 (2H), 0.96 (1H), 0.90 (3H), 0.87 (3H), 0.83 (3H) ppm.
17 mg (0,028 mmol) des nach Beispiel 2a dargestellten Silylethers werden in Analogie zu
Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 8 mg (0,018 mmol;
64%) der Titelverbindung als gelbliches Öl
¹H-NMR (400 MHz, CDCl₃): δ = 5,25-5,40 (5H), 5,38 (1H), 5,22 (1H), 4,97 (1H), 4,53
(1H), 3,16 (1H), 2,91 (1H), 2,68 (1H), 2,48 (1H), 2,32 (1H), 1,69 (1H), 1,43 (1H), 1,40
(9H), 1,32 (1H), 1,14 (3H), 0,97 (3H), 0,95 (3H) ppm.17 mg (0.028 mmol) of the silyl ether shown in Example 2a are reacted analogously to Example 1. After working up and purification, 8 mg (0.018 mmol; 64%) of the title compound are isolated as a yellowish oil
1 H-NMR (400 MHz, CDCl₃): δ = 5.25-5.40 (5H), 5.38 (1H), 5.22 (1H), 4.97 (1H), 4.53 (1H) , 3.16 (1H), 2.91 (1H), 2.68 (1H), 2.48 (1H), 2.32 (1H), 1.69 (1H), 1.43 (1H), 1.40 (9H), 1.32 (1H), 1.14 (3H), 0.97 (3H), 0.95 (3H) ppm.
Von dem nach Beispiel 1a dargestellten Silylether werden 52 mg (0,09 mmol) in 4 ml
Dichlormethan vorgelegt und mit 7,3 mg (0,09 mmol) Natriumcarbonat und 56 mg (0,18
mmol) 55%iger m-Chlorperbenzoesäure versetzt. Nach 2 Stunden Rühren bei 23°C
werden erneut 2 eq m-Chlorperbenzoesäure dazugegeben. Nach 4 Stunden wird die
Reaktion durch Zugabe von 1 M NaOH abgebrochen (DC-Kontrolle Methyl-t-
butylether/Petrolether 1 : 4, Rf = 0,47). Die wäßrige Phase wird dreimal mit
Dichlormethan extrahiert, die vereinigten organ. Phasen über Magnesiumsulfat
getrocknet, das Lösungsmittel im Vakuum abdestilliert und das Rohprodukt flash-
chromatographiert. Isoliert werden 17 mg (0,028 mmol, 31%) der Titelverbindung als
farbloses Öl.
¹H-NMR (400 MHz, CDCl₃): δ = 7,20-7,33 (5H), 5,55 (1H), 5,12 (1H), 4,92 (1H), 4,64
(1H), 2,81 (1H), 2,66 (1H), 2,46 (1H), 2,27 (1H), 1,65 (1H), 1,40 (11H), 1,12 (s;3H),
0,94 (3H), 0,92 (3H), 0,88 (21H) ppm.
52 mg (0.09 mmol) of the silyl ether prepared according to Example 1a are placed in 4 ml of dichloromethane, and 7.3 mg (0.09 mmol) of sodium carbonate and 56 mg (0.18 mmol) of 55% m-chloroperbenzoic acid are added . After 2 hours of stirring at 23 ° C, 2 eq m-chloroperbenzoic acid are added again. After 4 hours, the reaction is stopped by adding 1 M NaOH (TLC control methyl t-butyl ether / petroleum ether 1: 4, R f = 0.47). The aqueous phase is extracted three times with dichloromethane, the combined organ. Phases dried over magnesium sulfate, the solvent distilled off in vacuo and the crude product flash chromatographed. 17 mg (0.028 mmol, 31%) of the title compound are isolated as a colorless oil.
1 H-NMR (400 MHz, CDCl₃): δ = 7.20-7.33 (5H), 5.55 (1H), 5.12 (1H), 4.92 (1H), 4.64 (1H) , 2.81 (1H), 2.66 (1H), 2.46 (1H), 2.27 (1H), 1.65 (1H), 1.40 (11H), 1.12 (s; 3H) ), 0.94 (3H), 0.92 (3H), 0.88 (21H) ppm.
13 mg (0,019 mmol) des nach Beispiel 3a dargestellten Silylethers werden in Analogie zu
Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 4 mg (0,008 mmol;
40%) der Titelverbindung als farblose Kristalle.
¹H-NMR (400 MHz, CDCl₃: δ = 7,20-7,45 (10H), 5,21 (1H), 5,13 (1H), 4,74 (1H) 4,34
(1H), 3,03 (1H) 2,70 (1H), 2,63 (1H), 2,45 (1H), 1,37 (8H), 1,35 (1H), 1,22 (s;3H),
1,13 (3H), 1,02 (3H) ppm.13 mg (0.019 mmol) of the silyl ether shown in Example 3a are reacted analogously to Example 1. After working up and purification, 4 mg (0.008 mmol; 40%) of the title compound are isolated as colorless crystals.
1 H-NMR (400 MHz, CDCl₃: δ = 7.20-7.45 (10H), 5.21 (1H), 5.13 (1H), 4.74 (1H) 4.34 (1H), 3 , 03 (1H) 2.70 (1H), 2.63 (1H), 2.45 (1H), 1.37 (8H), 1.35 (1H), 1.22 (s; 3H), 1st , 13 (3H), 1.02 (3H) ppm.
Zu 104 mg (0,16 mmol) des nach Beispiel 3b dargestellten Silylethers in 2 ml t-Butanol
werden 0,1 ml Wasser und 12,8 µl Pyridin gegeben. Anschließend wird mit 24 mg (0,216
mmol) Trimethylamin-N-oxid (Dihydrat) und 24 µl einer 4%igen Lösung von OsO₄ in
Wasser (≈1 mg OsO₄) versetzt. Nach 68 Stunden Rühren bei 80°C (DC-Kotrolle;
Methyl-t-butylether/Petrolether 1 : 4; Rf = 0,26), konnte keine merkliche Verschiebung
des Reaktionsgleichgewichtes zu Gunsten des Produktes mehr beobachtet werden. Es
wird etwas Wasser zugegeben und fünfmal mit Methyl-t-butylether ausgeschüttelt. Die
vereinigten organischen Phasen werden über Magnesiumsulfat getrocknet, das
Lösungsmittel im Vakuum abdestilliert und das Rohprodukt flash-chromatographisch
gereinigt (Methyl-t-butylether/Petrolether 1 : 6). Isoliert werden 9 mg (0,013 mmol;
8,2%) der Titelverbindung als gelbes Öl
¹H-NMR (400 MHz,CDCl₃): δ = 7,15-7,50 (10H), 5,28 (2H), 4,60 (1H), 4,43 (1H), 2,66
(1H), 2,62 (1H), 2,41 (1H), 1,34 (10H), 1,22 (3H), 1,13 (3H), 1,05 (3H), 0,90 (21H)
ppm.0.1 ml of water and 12.8 μl of pyridine are added to 104 mg (0.16 mmol) of the silyl ether shown in Example 3b in 2 ml of t-butanol. Then 24 mg (0.216 mmol) trimethylamine N-oxide (dihydrate) and 24 µl of a 4% solution of OsO₄ in water (≈1 mg OsO₄) are added. After stirring at 80 ° C. for 68 hours (TLC control; methyl t-butyl ether / petroleum ether 1: 4; R f = 0.26), no noticeable shift in the reaction equilibrium in favor of the product could be observed. A little water is added and extracted five times with methyl t-butyl ether. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo and the crude product is purified by flash chromatography (methyl t-butyl ether / petroleum ether 1: 6). 9 mg (0.013 mmol; 8.2%) of the title compound are isolated as a yellow oil
1 H-NMR (400 MHz, CDCl₃): δ = 7.15-7.50 (10H), 5.28 (2H), 4.60 (1H), 4.43 (1H), 2.66 (1H) , 2.62 (1H), 2.41 (1H), 1.34 (10H), 1.22 (3H), 1.13 (3H), 1.05 (3H), 0.90 (21H) ppm .
45 mg (0,2 mmol) des nach Beispiel 3c dargestellten Alkohols werden in Analogie zu
Beispiel 1a umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 100 mg (0,15
mmol, 75%) der Titelverbindung als farbloses Öl.
¹H-NMR (400 MHz, CDCl₃): δ = 7,12-7,45 (10H), 5,82 (1H), 5,62 (1H), 5,33 (1H), 5,07
(1H), 4,53 (1H), 4,30 (1H), 4,05 (1H), 1,45 (9H), 1,06 (3H), 0,97 (1H), 0,92 (1H), 0,90
(3H), 0,83 (21H) ppm.
45 mg (0.2 mmol) of the alcohol shown in Example 3c are reacted analogously to Example 1a. After working up and purification, 100 mg (0.15 mmol, 75%) of the title compound are isolated as a colorless oil.
1 H-NMR (400 MHz, CDCl₃): δ = 7.12-7.45 (10H), 5.82 (1H), 5.62 (1H), 5.33 (1H), 5.07 (1H) , 4.53 (1H), 4.30 (1H), 4.05 (1H), 1.45 (9H), 1.06 (3H), 0.97 (1H), 0.92 (1H), 0.90 (3H), 0.83 (21H) ppm.
211 mg (0,93 mmol) des nach Beispiel 3d dargestellten Gemisches werden in 5 ml
wasserfreiem Et₂O unter Argonatmosphäre gelöst und mit 394 mg (= 0,35 ml, 2,78
mmol) einer 50%igen Lösung von BF₃ in Et₂O versetzt. Es wird über einen Zeitraum von
3 Stunden gerührt, wobei ein Farbumschlag von gelb nach braun zu beobachten ist. Zur
Aufarbeitung wird die organische Phase mit 5%iger Natriumcarbonat-Lösung gewaschen
und dreimal mit Methyl-t-butylether extrahiert. Nach dem Trocknen der vereinigten
organ. Phasen über Magnesiumsulfat wird das Lösungsmittel im Vakuum abdestilliert
und flash-chromatographisch gereinigt (Methyl-t-butylether/Petrolether 1 : 2). Isoliert
werden 69 mg (0,30 mmol, 64%) der Titelverbindung sowie 60 mg (0,29 mmol)
(1S,2R,4S)-2-Hydroxy-1,7,7-trimethyl-bicyclo[2.2.1]heptan-5-on jeweils als farblose
Kristalle.
¹H-NMR (400 MHz, CDCl₃): δ = 7,35 (5H), 6,01 (1H), 4,25 (1H), 2,80 (1H), 2,60 (1H),
1,20 (3H), 0,98 (1H), 0,90 (3H), 0,88 (3H) ppm.211 mg (0.93 mmol) of the mixture shown in Example 3d are dissolved in 5 ml of anhydrous Et₂O under an argon atmosphere and mixed with 394 mg (= 0.35 ml, 2.78 mmol) of a 50% solution of BF₃ in Et₂O. The mixture is stirred for a period of 3 hours, a color change from yellow to brown being observed. For working up, the organic phase is washed with 5% sodium carbonate solution and extracted three times with methyl t-butyl ether. After drying the combined organ. Phases over magnesium sulfate, the solvent is distilled off in vacuo and purified by flash chromatography (methyl t-butyl ether / petroleum ether 1: 2). 69 mg (0.30 mmol, 64%) of the title compound and 60 mg (0.29 mmol) (1S, 2R, 4S) -2-hydroxy-1,7,7-trimethyl-bicyclo [2.2.1] are isolated heptan-5-one each as colorless crystals.
1 H-NMR (400 MHz, CDCl₃): δ = 7.35 (5H), 6.01 (1H), 4.25 (1H), 2.80 (1H), 2.60 (1H), 1.20 (3H), 0.98 (1H), 0.90 (3H), 0.88 (3H) ppm.
Unter Argon werden 330 mg (1,57 mmol) des nach Beispiel 1c dargestellten Ketons in
12 ml wasserfreiem Tetrahydrofuran vorgelegt, auf -30°C abgekühlt und mit 8 ml (15,7
mmol) einer 20%igen Lösung von Phenyllithium in n-Hexan versetzt. Anschließend wird
langsam auf 23°C erwärmt und über Nacht gerührt. Zur Aufarbeitung wird auf 1 M.
Salzsäure gegeben und dreimal mit Methyl-t-butylether ausgeschüttelt. Die vereinigten
organischen Phasen werden über Magnesiumsulfat getrocknet, das Lösungsmittel im
Vakuum abdestilliert und das Rohprodukt flash-chromatographisch gereinigt (Methyl-t-
butylether/Petrolether 1 : 1; Rf = 0,12). Isoliert werden 211 mg (0,93 mmol) eines 1 : 1-
Gemisches der Titelverbindung und (1S,2R,4S)-2-Hydroxy-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-5-on, welches ohne Trennung weiter umgesetzt wird.
¹H-NMR (400 MHz, CDCl₃): δ = 6,25-6,51 (5H), 4,23 (1H), 4,03 (1H), 2,62 (1H), 2,56
(1H), 2,50 (1H), 2,32 (1H), 2,27 (1H), 2,23 (1H), 2,14 (1H), 2,07 (1H), 1,90 (1H), 1,81
(1H), 1,30 (1H), 1,02 (3H), 0,96 (6H), 0,94 (3H), 0,93 (3H), 0,87 (3H) ppm.Under argon, 330 mg (1.57 mmol) of the ketone shown in Example 1c are placed in 12 ml of anhydrous tetrahydrofuran, cooled to -30 ° C. and mixed with 8 ml (15.7 mmol) of a 20% solution of phenyllithium in n- Hexane added. The mixture is then slowly warmed to 23 ° C. and stirred overnight. For working up, 1 M hydrochloric acid is added and the mixture is extracted three times with methyl t-butyl ether. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo and the crude product is purified by flash chromatography (methyl t-butyl ether / petroleum ether 1: 1; R f = 0.12). 211 mg (0.93 mmol) of a 1: 1 mixture of the title compound and (1S, 2R, 4S) -2-hydroxy-1,7,7-trimethyl-bicyclo [2.2.1] heptan-5-one are isolated , which is implemented without separation.
1 H-NMR (400 MHz, CDCl₃): δ = 6.25-6.51 (5H), 4.23 (1H), 4.03 (1H), 2.62 (1H), 2.56 (1H) , 2.50 (1H), 2.32 (1H), 2.27 (1H), 2.23 (1H), 2.14 (1H), 2.07 (1H), 1.90 (1H), 1.81 (1H), 1.30 (1H), 1.02 (3H), 0.96 (6H), 0.94 (3H), 0.93 (3H), 0.87 (3H) ppm.
20 mg (0,031 mmol) des nach Beispiel 4a dargestellten Silylethers werden in Analogie zu
Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 9 mg (0,018 mmol;
59%) der Titelverbindung als farbloses Öl.
¹H-NMR (400MHz, CDCl₃): δ = 6,95-7,57 (10H), 6,12 (1H) 5,95 (1H), 5,21 (1H), 4,99
(1H), 4,42 (1H), 3,02 (1H), 2,88 (1H), 2,54 (1H), 1,45 (9H), 1,17 (3H), 1,02 (3H), 0,94
(3H) ppm.20 mg (0.031 mmol) of the silyl ether shown in Example 4a are reacted analogously to Example 1. After working up and purification, 9 mg (0.018 mmol; 59%) of the title compound is isolated as a colorless oil.
1 H-NMR (400MHz, CDCl₃): δ = 6.95-7.57 (10H), 6.12 (1H) 5.95 (1H), 5.21 (1H), 4.99 (1H), 4th , 42 (1H), 3.02 (1H), 2.88 (1H), 2.54 (1H), 1.45 (9H), 1.17 (3H), 1.02 (3H), 0, 94 (3H) ppm.
45 mg (0,2 mmol) des nach Beispiel 3c dargestellten Alkohols werden in Analogie zu
Beispiel 1a umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 100 mg (0,15
mmol, 75%) der Titelverbindung als farbloses Öl.
¹H-NMR (400 MHz, CDCl₃): δ = 7,12-7,45 (10H), 5,82 (1H), 5,62 (1H), 5,33 (1H), 5,07
(1H), 4,53 (1H), 4,30 (1H), 4,05 (1H), 1,45 (9H), 1,06 (3H), 0,97 (1H), 0,92 (s;1H),
0,90 (3H), 0,83 (21H) ppm.45 mg (0.2 mmol) of the alcohol shown in Example 3c are reacted analogously to Example 1a. After working up and purification, 100 mg (0.15 mmol, 75%) of the title compound are isolated as a colorless oil.
1 H-NMR (400 MHz, CDCl₃): δ = 7.12-7.45 (10H), 5.82 (1H), 5.62 (1H), 5.33 (1H), 5.07 (1H) , 4.53 (1H), 4.30 (1H), 4.05 (1H), 1.45 (9H), 1.06 (3H), 0.97 (1H), 0.92 (s; 1H ), 0.90 (3H), 0.83 (21H) ppm.
24 mg (0,036 mmol) des nach Beispiel 5a dargestellten Silylethers werden in Analogie zu
Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 9 mg (0,018 mmol;
50%) der Titelverbindung mit einem Diastereomerenverhältnis (5R):(5S) = 1 : 2 als
farblose Kristalle.
¹H-NMR (400 MHz, CDCl₃): δ = 7,17-7,55 (5H), 5,32 (2H), 5,16 (3H), 4,87 (1H), 4,51
(1H), 4,43 (1H), 3,96 (1H), 3,55 (1H), 3,20 (1H), 3,12 (1H), 2,89 (2H), 2,57 (1H), 2,35
(1H), 1,56 (2H), 1,39 (9H), 1,35 (9H), 1,06 (6H), 1,04 (6H), 0,99 (6H) ppm.24 mg (0.036 mmol) of the silyl ether shown in Example 5a are reacted analogously to Example 1. After working up and purification, 9 mg (0.018 mmol; 50%) of the title compound with a diastereomer ratio (5R) :( 5S) = 1: 2 are isolated as colorless crystals.
1 H-NMR (400 MHz, CDCl₃): δ = 7.17-7.55 (5H), 5.32 (2H), 5.16 (3H), 4.87 (1H), 4.51 (1H) , 4.43 (1H), 3.96 (1H), 3.55 (1H), 3.20 (1H), 3.12 (1H), 2.89 (2H), 2.57 (1H), 2.35 (1H), 1.56 (2H), 1.39 (9H), 1.35 (9H), 1.06 (6H), 1.04 (6H), 0.99 (6H) ppm.
12 mg (0,08 mmol) des nach Beispiel 5b dargestellten Alkohols werden in Analogie zu
Beispiel 1a umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 24 mg (0,036
mmol; 45%) der Titelverbindung als gelbes Öl.
¹H-NMR (400 MHz, CDCl₃): δ = 7,18-7,40 (10H), 5,37 (2H), 4,87 (1H), 4,52 (1H), 3,97
(1H), 2,52 (1H), 2,28 (1H), 1,37 (10H), 1,06 (3H), 1,04 (3H), 0,99 (3H), 0,91 (21H)
ppm.
12 mg (0.08 mmol) of the alcohol shown in Example 5b are reacted analogously to Example 1a. After working up and purification, 24 mg (0.036 mmol; 45%) of the title compound are isolated as a yellow oil.
1 H-NMR (400 MHz, CDCl₃): δ = 7.18-7.40 (10H), 5.37 (2H), 4.87 (1H), 4.52 (1H), 3.97 (1H) , 2.52 (1H), 2.28 (1H), 1.37 (10H), 1.06 (3H), 1.04 (3H), 0.99 (3H), 0.91 (21H) ppm .
35 mg (0,15 mmol) des nach Beispiel 3c dargestellten Alkohols werden in 2 ml
Dichlormethan vorgelegt und bei 23°C mit 93 mg (0,30 mmol) m-Chlorperbenzoesäure
(55%ig) versetzt. Nach 2 Stunden und nach 4 Stunden werden noch jeweils 2 eq m-
Chlorperbenzoesäure dazugegeben (DC-Kontrolle; Methyl-t-butylether/Petrolether 1 : 1;
Rf = 0,47). Nach 5 Stunden Rühren bei 23°C wird die Reaktion abgebrochen. Es wird
mit 1 M NaOH gewaschen und die wäßrige Phase dreimal mit Dichlormethan extrahiert.
Die vereinigten organischen Phasen werden über Magnesiumsulfat getrocknet, das
Lösungsmittel im Vakuum abdestilliert und das Rohprodukt flash-chromatographisch
gereinigt (Methyl-t-butylether/Petrolether 1 : 4). Isoliert werden 10 mg (0,041 mmol,
27%) der Titelverbindung als farbloses Öl.
¹H-NMR (400 MHz, CDCl₃): δ = 7,19-7,35 (5H), 4,30 (1H), 3,91 (1H), 2,43 (1H), 2,27
(1H), 1,45 (1H), 1,08 (3H), 1,06 (3H), 1,02 (3H) ppm.35 mg (0.15 mmol) of the alcohol shown in Example 3c are placed in 2 ml of dichloromethane and 93 mg (0.30 mmol) of m-chloroperbenzoic acid (55%) are added at 23 ° C. After 2 hours and after 4 hours, 2 eq m-chloroperbenzoic acid are added (TLC control; methyl t-butyl ether / petroleum ether 1: 1; R f = 0.47). After 5 hours of stirring at 23 ° C., the reaction is stopped. It is washed with 1 M NaOH and the aqueous phase extracted three times with dichloromethane. The combined organic phases are dried over magnesium sulfate, the solvent is distilled off in vacuo and the crude product is purified by flash chromatography (methyl t-butyl ether / petroleum ether 1: 4). 10 mg (0.041 mmol, 27%) of the title compound are isolated as a colorless oil.
1 H-NMR (400 MHz, CDCl₃): δ = 7.19-7.35 (5H), 4.30 (1H), 3.91 (1H), 2.43 (1H), 2.27 (1H) , 1.45 (1H), 1.08 (3H), 1.06 (3H), 1.02 (3H) ppm.
427 mg (max. 0,65 mmol) des nach Beispiel 6a dargestellten Silylethers werden in
Analogie zu Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 242
mg (0,58 mmol, 89%) der Titelverbindung als farbloses Öl.
¹H-NMR (300 MHz, CDCl₃): δ = 7,22-7,48 (5H), 5,43 (1H), 5,27 (1H), 4,95 (1H), 4,51
(1H), 3,18 (1H), 2,38 (1H), 1,99 (1H), 1,25-1,85 (13H), 0,80-1,15 (10H) ppm.427 mg (max. 0.65 mmol) of the silyl ether shown in Example 6a are reacted analogously to Example 1. After working up and purification, 242 mg (0.58 mmol, 89%) of the title compound are isolated as a colorless oil.
1 H-NMR (300 MHz, CDCl₃): δ = 7.22-7.48 (5H), 5.43 (1H), 5.27 (1H), 4.95 (1H), 4.51 (1H) , 3.18 (1H), 2.38 (1H), 1.99 (1H), 1.25-1.85 (13H), 0.80-1.15 (10H) ppm.
100 mg (0,65 mmol) (1R)-(+)-Borneol werden in Analogie zu Beispiel 1a umgesetzt. Nach Aufarbeitung isoliert man 427 mg der Titelverbindung als Rohprodukt, das ohne Reinigung weiter umgesetzt wird.100 mg (0.65 mmol) (1R) - (+) - borneol are reacted analogously to Example 1a. After working up, 427 mg of the title compound is isolated as a crude product without Cleaning is implemented further.
443 mg (max. 0,65 mmol) des nach Beispiel 7a dargestellten Silylethers werden in
Analogie zu Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 158
mg (0,37 mmol, 58%) der Titelverbindung als farbloses Öl.
¹H-NMR (300 MHz, CDCl₃): δ = 7,76 (2H), 7,22-7,55 (8H), 6,98 (1H), 5,80 (1H), 4,93
(1H), 4,68 (1H), 3,32 (1H), 2,29 (1H), 2,00 (1H), 1,74 (1H), 1,63 (1H), 1,20-1,44 (2H),
0,81-0,98 (10H) ppm.443 mg (max. 0.65 mmol) of the silyl ether prepared according to Example 7a are reacted analogously to Example 1. After working up and purifying, 158 mg (0.37 mmol, 58%) of the title compound are isolated as a colorless oil.
1 H-NMR (300 MHz, CDCl₃): δ = 7.76 (2H), 7.22-7.55 (8H), 6.98 (1H), 5.80 (1H), 4.93 (1H) , 4.68 (1H), 3.32 (1H), 2.29 (1H), 2.00 (1H), 1.74 (1H), 1.63 (1H), 1.20-1.44 (2H), 0.81-0.98 (10H) ppm.
100 mg (0,65 mmol) (1R)-(+)-Borneol werden in Analogie zu Beispiel 1a unter Verwendung von (3R,4S)-1-benzoyl-3-triisopropylsilyloxy-4-phenyl-2-azetidinon umgesetzt. Nach Aufarbeitung isoliert man 443 mg der Titelverbindung als Rohprodukt, das ohne Reinigung weiter umgesetzt wird.100 mg (0.65 mmol) (1R) - (+) - Borneol are analogous to Example 1a under Use of (3R, 4S) -1-benzoyl-3-triisopropylsilyloxy-4-phenyl-2-azetidinone implemented. After working up, 443 mg of the title compound is isolated as a crude product, that is implemented without cleaning.
412 mg (max. 0,65 mmol) des nach Beispiel 8a dargestellten Silylethers werden in
Analogie zu Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 247
mg (0,59 mmol, 91%) der Titelverbindung als farbloses Öl.
¹H-NMR (300 MHz, CDCl₃): δ = 7,21-7,45 (5H), 5,44 (1H), 5,22 (1H), 5,08 (1H), 4,48
(1H), 3,16 (1H), 2,38 (1H), 1,96 (1H), 1,79 (1H), 1,73 (1H), 1,20-1,50 (11H), 1,06
(1H), 0,94 (3H), 0,89 (3H), 0,87 (3H) ppm.412 mg (max. 0.65 mmol) of the silyl ether shown in Example 8a are reacted analogously to Example 1. After working up and purification, 247 mg (0.59 mmol, 91%) of the title compound are isolated as a colorless oil.
1 H-NMR (300 MHz, CDCl₃): δ = 7.21-7.45 (5H), 5.44 (1H), 5.22 (1H), 5.08 (1H), 4.48 (1H) , 3.16 (1H), 2.38 (1H), 1.96 (1H), 1.79 (1H), 1.73 (1H), 1.20-1.50 (11H), 1.06 (1H), 0.94 (3H), 0.89 (3H), 0.87 (3H) ppm.
100 mg (0,65 mmol) (1S)-(-)-Borneol werden in Analogie zu Beispiel 1a umgesetzt. Nach Aufarbeitung isoliert man 412 mg der Titelverbindung als Rohprodukt, das ohne Reinigung weiter umgesetzt wird.100 mg (0.65 mmol) (1S) - (-) - borneol are reacted analogously to Example 1a. After working up, 412 mg of the title compound is isolated as a crude product without Cleaning is implemented further.
401 mg (max. 0,65 mmol) des nach Beispiel 9a dargestellten Silylethers werden in
Analogie zu Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 258
mg (0,61 mmol, 94%) der Titelverbindung als farbloses Öl.
¹H-NMR (300 MHz, CDCl₃): δ = 7,77 (2H), 7,24-7,55 (8H), 7,02 (1H), 5,73 (1H), 5,03
(1H), 4,65 (1H), 3,30 (1H), 2,38 (1H), 1,95 (1H), 1,78 (1H), 1,71 (1H), 1,18-1,43 (2H),
1,03 (1H), 0,89 (3H), 0,86 (3H), 0,79 (3H) ppm.
401 mg (max. 0.65 mmol) of the silyl ether prepared according to Example 9a are reacted analogously to Example 1. After working up and purification, 258 mg (0.61 mmol, 94%) of the title compound are isolated as a colorless oil.
1 H-NMR (300 MHz, CDCl₃): δ = 7.77 (2H), 7.24-7.55 (8H), 7.02 (1H), 5.73 (1H), 5.03 (1H) , 4.65 (1H), 3.30 (1H), 2.38 (1H), 1.95 (1H), 1.78 (1H), 1.71 (1H), 1.18-1.43 (2H), 1.03 (1H), 0.89 (3H), 0.86 (3H), 0.79 (3H) ppm.
100 mg (0,65 mmol) (1S)-(-)-Borneol werden in Analogie zu Beispiel 1a unter Verwendung von (3R,4S)-1-benzoyl-3-triisopropylsilyloxy-4-phenyl-2-azetidinon umgesetzt. Nach Aufarbeitung isoliert man 401 mg der Titelverbindung als Rohprodukt, das ohne Reinigung weiter umgesetzt wird.100 mg (0.65 mmol) (1S) - (-) - Borneol are analogous to Example 1a Use of (3R, 4S) -1-benzoyl-3-triisopropylsilyloxy-4-phenyl-2-azetidinone implemented. After working up, 401 mg of the title compound is isolated as a crude product, that is implemented without cleaning.
43 mg (73 µmol) des nach Beispiel 10a dargestellten Silylethers werden in Analogie zu
Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 17 mg (39 µmol,
54%) der Titelverbindung als farblosen amorphen Feststoff.
¹H-NMR (200 MHz, CDCl₃): δ = 7,36 (5H), 5,21 (1H), 5,20 (1H), 4,86 (1H), 4,50 (1H),
4,00 (1H), 2,40 (1H), 1,78 (1H), 1,52 (1H), 1,38 (9H), 1,18 (3H), 0,90 (7H) ppm.43 mg (73 μmol) of the silyl ether shown in Example 10a are reacted analogously to Example 1. After working up and purification, 17 mg (39 μmol, 54%) of the title compound are isolated as a colorless amorphous solid.
1 H-NMR (200 MHz, CDCl₃): δ = 7.36 (5H), 5.21 (1H), 5.20 (1H), 4.86 (1H), 4.50 (1H), 4.00 (1H), 2.40 (1H), 1.78 (1H), 1.52 (1H), 1.38 (9H), 1.18 (3H), 0.90 (7H) ppm.
40 mg (0,23 mmol) des nach Beispiel 10b dargestellten Diols werden in Analogie zu
Beispiel 1a umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 32 mg (0,054
mmol; 23%) der Titelverbindung als farblosen amorphen Feststoff.
¹H-NMR (200 MHz, CDCl₃): δ = 7,28 (5H), 5,52 (1H), 5,10 (1H), 4,82 (1H), 4,56 (1H),
3,93 (1H), 2,38 (2H), 1,76 (1H), 1,60-0,80 (32H) ppm.40 mg (0.23 mmol) of the diol shown in Example 10b are reacted analogously to Example 1a. After working up and purification, 32 mg (0.054 mmol; 23%) of the title compound are isolated as a colorless amorphous solid.
1 H-NMR (200 MHz, CDCl₃): δ = 7.28 (5H), 5.52 (1H), 5.10 (1H), 4.82 (1H), 4.56 (1H), 3.93 (1H), 2.38 (2H), 1.76 (1H), 1.60-0.80 (32H) ppm.
170 mg (0,8 mmol) des nach Beispiel 1c dargestellten Acetates werden unter
Stickstoffatmosphäre in 6 ml wasserfreiem Diethylether gelöst, mit 50 mg
Lithiumaluminiumhydrid versetzt und eine Stunde bei 23°C gerührt. Anschließend
werden unter Eiskühlung zuerst 5 Tropfen Methanol anschließend so lange tropfenweise
Wasser zugegeben, bis sich ein feinkörniger Niederschlag gebildet hat. Den nach
Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch
Chromatographie an Kieseigel mit einem Laufmittelgemisch aus Methyl-tert.-butylether
und Petrolether. Isoliert werden 93 mg (0,55 mmol, 68%) der Titelverbindung als
farblose Kristalle.
¹H-NMR (200 MHz, CDCl₃): δ = 3,90 (2H), 2,30 (2H), 1,72 (1H), 1,38 (1H), 1,12 (3H),
0,91 (3H), 0,86 (3H), 0,78 (1H) ppm.170 mg (0.8 mmol) of the acetate shown in Example 1c are dissolved in 6 ml of anhydrous diethyl ether under a nitrogen atmosphere, 50 mg of lithium aluminum hydride are added and the mixture is stirred at 23 ° C. for one hour. 5 drops of methanol are then added dropwise, while cooling with ice, until a drop of fine-grained precipitate has formed. The residue obtained after filtration and removal of solvent is purified by chromatography on silica gel using a mobile phase mixture of methyl tert-butyl ether and petroleum ether. 93 mg (0.55 mmol, 68%) of the title compound are isolated as colorless crystals.
1 H-NMR (200 MHz, CDCl₃): δ = 3.90 (2H), 2.30 (2H), 1.72 (1H), 1.38 (1H), 1.12 (3H), 0.91 (3H), 0.86 (3H), 0.78 (1H) ppm.
Claims (3)
R¹ einen gegebenenfalls durch Halogenatome, C₁-C₄-Alkylgruppen, C₁-C₄- Alkoxygruppen, C₁-C₆-Alkoxycarbonylgruppen oder C₁-C₈- Acyloxygruppen substituierter Phenylrest darstellt,
R² ein Wasserstoffatom, eine C₁-C₄-Alkylgruppe, substituiertes Aryl, eine C₁- C₆-Alkoxycarbonylgruppe oder eine C₁-C₈-Acylgruppe symbolisiert,
R³ ein Wasserstoffatom, eine C₁-C₄-Alkylgruppe, eine C₁-C₄-Acylgruppe oder eine Tri-C₁-C₄-alkylsilylgruppe bedeutet und worin
R⁴ und R⁷ ein Wasserstoffatom, einen C₁-C₄-Alkylrest oder einen gegebenenfalls durch Halogenatome, C₁-C₄-Alkylgruppe, C₁-C₉-Alkoxygruppen, C₁-C₄- Alkoxycarbonylgruppen oder C₁-C₈-Acyloxygruppen substituierter Phenylrest bedeuten und
R⁵ und R⁶ ein Wasserstoffatom, eine Hydroxygruppe, oder eine C₁-C₈-Acyloxygruppe darstellen oder gemeinsam eine Kohlenstoff-Kohlenstoffbindung oder ein Sauerstoffatom symbolisieren oder
R⁴ und R⁵ und/oder R⁶ und R⁷ jeweils gemeinsam eine Carbonylgruppe, eine C₁-C₄- Alkylidengruppe oder gewünschtenfalls durch eine C₁-C₃-Alkylgruppe substituierte Oxirangruppe bedeuten,
sowie gegebenenfalls deren Salze mit physiologisch verträglichen Säuren, sowie deren α-, β- oder γ-Cyclodextrinclathrateund die in Liposomen verkapselten Verbindungen der allgemeinen Formel I bedeuten.1. The borneol derivatives of the general formula I wherein
R¹ represents a phenyl radical optionally substituted by halogen atoms, C₁-C₄ alkyl groups, C₁-C₄ alkoxy groups, C₁-C₆ alkoxycarbonyl groups or C₁-C₈ acyloxy groups,
R² symbolizes a hydrogen atom, a C₁-C₄-alkyl group, substituted aryl, a C₁-C₆-alkoxycarbonyl group or a C₁-C₈-acyl group,
R³ represents a hydrogen atom, a C₁-C₄-alkyl group, a C₁-C₄-acyl group or a tri-C₁-C₄-alkylsilyl group and wherein
R⁴ and R⁷ represent a hydrogen atom, a C₁-C₄ alkyl radical or a phenyl radical which is optionally substituted by halogen atoms, C₁-C₄ alkyl group, C₁-C₉ alkoxy groups, C₁-C₄ alkoxycarbonyl groups or C₁-C₈ acyloxy groups and
R⁵ and R⁶ represent a hydrogen atom, a hydroxy group, or a C₁-C₈ acyloxy group or together symbolize a carbon-carbon bond or an oxygen atom or
R⁴ and R⁵ and / or R⁶ and R⁷ each together represent a carbonyl group, a C₁-C₄ alkylidene group or, if desired, an oxirane group substituted by a C₁-C₃ alkyl group,
and optionally their salts with physiologically compatible acids, and their α-, β- or γ-cyclodextrin clathrates and the compounds of the general formula I encapsulated in liposomes.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19509697A DE19509697A1 (en) | 1995-03-08 | 1995-03-08 | New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv. |
PCT/EP1996/001324 WO1997035839A1 (en) | 1995-03-08 | 1996-03-27 | Novel borneols, processes for producing them and pharmaceutical use thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19509697A DE19509697A1 (en) | 1995-03-08 | 1995-03-08 | New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv. |
PCT/EP1996/001324 WO1997035839A1 (en) | 1995-03-08 | 1996-03-27 | Novel borneols, processes for producing them and pharmaceutical use thereof |
Publications (1)
Publication Number | Publication Date |
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DE19509697A1 true DE19509697A1 (en) | 1996-09-12 |
Family
ID=26013466
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DE19509697A Withdrawn DE19509697A1 (en) | 1995-03-08 | 1995-03-08 | New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv. |
Country Status (2)
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DE (1) | DE19509697A1 (en) |
WO (1) | WO1997035839A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997035839A1 (en) * | 1995-03-08 | 1997-10-02 | Schering Aktiengesellschaft | Novel borneols, processes for producing them and pharmaceutical use thereof |
CN108558621A (en) * | 2018-05-17 | 2018-09-21 | 华南理工大学 | A kind of two bornyl acetal derivant of citral and preparation method thereof and purposes |
CN113845424A (en) * | 2021-10-14 | 2021-12-28 | 南京医科大学 | Right camphol ester compound and pharmaceutical application thereof |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1212055B1 (en) | 1999-08-16 | 2011-08-03 | Revaax Pharmaceuticals LLC | Neurotherapeutic composition comprising a beta-lactam compound |
WO2006120495A1 (en) * | 2005-05-13 | 2006-11-16 | Advanced Scientific Developements | Pharmaceutical composition comprising an antiviral agent, an antitumour agent or an antiparasitic agent and an active substance selected from carveol, thymol, eugenol, borneol and carvacrol |
CN104276947B (en) * | 2014-09-19 | 2017-03-15 | 江西省林业科学院 | A kind of method that natural d-borneol prepares dextrorotation Bronyl acetate |
Family Cites Families (4)
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FR2601676B1 (en) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL |
RU2128654C1 (en) * | 1991-09-23 | 1999-04-10 | Флорида Стейт Юниверсити | Method of preparing taxane |
DE4416374A1 (en) * | 1994-05-05 | 1995-11-09 | Schering Ag | New borneol derivatives, processes for their production and their pharmaceutical use |
DE19509697A1 (en) * | 1995-03-08 | 1996-09-12 | Schering Ag | New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv. |
-
1995
- 1995-03-08 DE DE19509697A patent/DE19509697A1/en not_active Withdrawn
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1996
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997035839A1 (en) * | 1995-03-08 | 1997-10-02 | Schering Aktiengesellschaft | Novel borneols, processes for producing them and pharmaceutical use thereof |
CN108558621A (en) * | 2018-05-17 | 2018-09-21 | 华南理工大学 | A kind of two bornyl acetal derivant of citral and preparation method thereof and purposes |
CN108558621B (en) * | 2018-05-17 | 2021-01-19 | 华南理工大学 | Citral di-bornyl acetal derivative and preparation method and application thereof |
CN113845424A (en) * | 2021-10-14 | 2021-12-28 | 南京医科大学 | Right camphol ester compound and pharmaceutical application thereof |
CN113845424B (en) * | 2021-10-14 | 2023-09-12 | 南京医科大学 | Right-embedding alcohol ester compound and its pharmaceutical use |
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