WO1997035839A1 - Novel borneols, processes for producing them and pharmaceutical use thereof - Google Patents

Novel borneols, processes for producing them and pharmaceutical use thereof Download PDF

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Publication number
WO1997035839A1
WO1997035839A1 PCT/EP1996/001324 EP9601324W WO9735839A1 WO 1997035839 A1 WO1997035839 A1 WO 1997035839A1 EP 9601324 W EP9601324 W EP 9601324W WO 9735839 A1 WO9735839 A1 WO 9735839A1
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group
alkyl
general formula
mmol
groups
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PCT/EP1996/001324
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German (de)
French (fr)
Inventor
Ulrich Klar
Hermann Graf
Siegfried Blechert
Anke Sachse
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Schering Aktiengesellschaft
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Priority to PCT/EP1996/001324 priority patent/WO1997035839A1/en
Publication of WO1997035839A1 publication Critical patent/WO1997035839A1/en

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    • 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

Definitions

  • the invention relates to new pharmacologically active compounds which have the ability to influence tubulin polymerization or tubulin depolymerization.
  • mitotic poisons are used as antitumor agents or are in clinical trials.
  • Mitotic poisons have a certain selectivity for tumor cells due to the physicochemical properties that have not yet been understood and the special features of neoplastic cells.
  • Taxanes have recently opened up important areas of application that were not accessible due to the cytostatics available to date, e.g. Ovarian cancer, malignant melanoma. However, the side effects of taxanes are comparable to those of other cytostatics (e.g. hair loss, sensory neuropathy). Multi-drug resistant tumor cells that overexpress the P-glycoprotein are resistant to taxanes. The limited availability of the natural product taxol also hinders broader clinical testing.
  • Tubulin is an essential part of the mitotic spindle. Among other things, it serves to maintain the cell shape, to transport organelles within the cell and to influence cell mobility.
  • taxanes have been the only known structural class that is able to accelerate the polymerization of tubulin (predominantly in the G2 phase) and the stabilize formed microtubule polymers. This mechanism differs significantly from those that have other structural classes that also influence phase-specific cell division. For example, substances from the group of vinca alkaloids (eg vincristine and vinblastine) but also colchicine inhibit the polymerization of the tubulin dimers in the M phase.
  • vinca alkaloids eg vincristine and vinblastine
  • R 1 a optionally by halogen atoms, -CC4-alkyl groups, C1-C4-
  • Phenyl radical substituted by acyloxy groups is a hydrogen atom, a substituted aryl, aC r
  • R 3 represents a hydrogen atom, a C r C 4 alkyl group, a C 1 -C 4 acyl group or a means and wherein R 4 and R 7 is a hydrogen atom, a C r C 4 alkyl radical or an optionally by
  • Halogen atoms C 1 -C 4 alkyl group, C r C 9 alkoxy groups, C 1 -C 4 -
  • Phenyl radical and R 5 and R 6 represent a hydrogen atom, a hydroxy group, or a C 1 -Cg acyloxy group or together represent a carbon-carbon bond or a
  • R 4 and R 5 and / or R 6 and R 7 each together represent a carbonyl group, a C 1 -C 4 -
  • the invention relates to the diastereomers and / or enantiomers of these borneol derivatives and also mixtures thereof.
  • Straight or branched-chain groups are to be considered as alkyl groups of these borneol derivatives, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-
  • aryl radical of these compounds there are alicyclic, carbocyclic or heterocyclic radicals such as e.g. Phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl,
  • Such substituents are, for example, alkoxy, acyl and acyloxy groups, where
  • Propionyl. and isopropionyl groups are preferred.
  • Free hydroxyl groups can be functionally modified, for example by
  • radicals known to the person skilled in the art are suitable as ether and acyl radicals.
  • Tetrahydroruranyl tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl.
  • acyl residues e.g. Acetyl, propionyl, butyryl, benzoyl in question.
  • Halogen in the definitions for X means fluorine, chlorine, bromine and iodine.
  • Inorganic and organic acids as are known to the person skilled in the art for the formation of physiologically tolerable salts, are suitable for salt formation with the free bases.
  • the 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
  • R 4 , R 5 , R 6 and R 7 have the abovementioned meanings and hydroxyl groups contained in R 5 or R 6 are optionally protected, with a la ⁇ am of the general formula lilac or a carboxyl compound of the general formula Illb,
  • R 1 , R ⁇ and R ⁇ in the abovementioned meaning and X 'in the meaning OH, O- C (0) -CH (OR 2 ) -CH (NHR 2 ) -R 1 , halogen or C r C 10 -Alkyl and may be protected in purple or Illb contained hydroxyl groups, esterified, any existing double bonds oxidized, protected hydroxyl groups released and converted into a derivative of general formula I.
  • a base such as e.g. Metal hydrides (e.g. sodium hydride), alkali alcoholates (e.g. sodium methoxide, potassium tert-butoxide), alkali hexamethyldisilazane (e.g. sodium hexamethyldisilazane), 1.5-
  • Metal hydrides e.g. sodium hydride
  • alkali alcoholates e.g. sodium methoxide, potassium tert-butoxide
  • alkali hexamethyldisilazane e.g. sodium hexamethyldisilazane
  • an inert solvent such as e.g. Dichloromethane, diethyl ether, tetrahydrofuran at -70 ° C to + 50 ° C implemented.
  • R 6 and R 7 together represent an alkylidene group the functionalization of the olefinic double bond can be carried out by the methods known to the person skilled in the art.
  • hydrogen can be added, for example by cat.
  • Hydrogenation, hydroxyl groups can be introduced by water addition (hydroboration, oxymercuration) or by 1,2-bishydroxylation, for example with osmium tetroxide or potassium permanganate.
  • a carbonyl group can be introduced, for example, by oxidation of a hydroxyl group.
  • the epoxide can be formed 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 For example, hydrogen chloride, para-toluenesulfonic acid or Lewis acids, such as, for example, boron trifluoride etherate, titanium tetraisopropoxide, cerium ammonium nitrate, can be cleaved either in inert solvents or solvents which function as a nucleophile at -70 ° C. to + 50 ° C.
  • 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 For example, hydrogen chloride, para-toluenesulfonic acid or Lewis acids, such as, for example, boron trifluoride etherate, titanium te
  • 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.
  • active substances of this type are suitable for the treatment of diseases in which the influencing of cell division can be indicated therapeutically, such as e.g. 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 classes of substances which can be used in tumor therapy. Examples include the combination with O platinum complexes such as Cisplatin, carboplatin, O intercalating substances e.g. from the class of anthracyclines such as
  • Taxotere or from the macrolide class such as Rhizoxin or others
  • Connections such as Colchicine, combretastatin A-4, O DNA topoisomerase inhibitors such as e.g. Camptothecin, etoposide, topotecan,
  • Somatostatin Somatostatin, suramin, bombesin antagonists, O inhibitors of protein tyrosine kinase or protein kinases A or C such as e.g.
  • Antiandrogens such as, for example, cyproterone acetate, O metastasis-inhibiting compounds, for example from the class of the eicosanoids, such as PGI 2 , PGEj, 6-oxo-PGEi and their stable derivatives (for example iloprost,
  • Cicaprost, beraprost), O inhibitors of the transmembrane Ca 2+ influx such as verapamil, galopamil,
  • neuroleptics such as e.g. Chlorpromazin, Trifuoperazin, Thioridazin, Pe ⁇ henazin, O local anesthetics like e.g. Carbanilate-Ca7, cinchocaine, carbanilate-Ca3, articaine,
  • Carbanilate, lidocaine O substances that inhibit angiogenesis, e.g. anti-VEGF antibodies,
  • Endostatin B interferon ⁇
  • AGM 1470 O inhibitors of cell proliferation in psoriasis, Kaposisarcom, neuroblastoma.
  • the invention also relates to pharmaceuticals based on the pharmaceutically acceptable, i.e. in the doses used, non-toxic borneol derivatives of the general formula I, if appropriate together with the customary auxiliaries and carriers.
  • the compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragées, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
  • the active ingredient (s) can be combined with the auxiliaries commonly used in galenics, e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifying agents, preservatives and flavoring agents for flavor correction (for example essential oils) become.
  • auxiliaries commonly used in galenics e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifying agents, preservatives and flavoring agents for flavor correction (for example essential oils) become.
  • the invention thus also relates to pharmaceutical compositions which contain at least one compound according to the invention as active ingredient.
  • One dose unit contains about 0.1-100 mg of active ingredient (s).
  • the dosage of the compounds according to the invention in humans is about 0.1-1000 mg per day.
  • Example 2a 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
  • Example 3a 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.
  • Example 3c 45 mg (0.2 mmol) of the alcohol shown in Example 3c are reacted analogously to Example la. After working up and purification, 100 mg (0.15 mmol, 75%) of the title compound are isolated as a colorless oil.
  • Example 1c 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.
  • Example 4a 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.
  • ⁇ -NMR (400MHz, CDC1 3 ): ⁇ 6.95-7.57 (10H), 6.12 (1H) 5.95 (IH), 5.21 (IH), 4.99 (IH), 4.42 (IH), 3.02 (IH), 2.88 (IH), 2.54 (IH), 1.45 (9H), 1.17 (3H), 1.02 (3H), 0 , 94 (3H) ppm.
  • Example 3c 45 mg (0.2 mmol) of the alcohol shown in Example 3c are reacted analogously to Example la. After working up and purification, 100 mg (0.15 mmol, 75%) of the title compound are isolated as a colorless oil.
  • Example la implemented. After working up and purification, 24 mg (0.036 mmol; 45%) of the title compound are isolated as a yellow oil.
  • Example 6a 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.
  • Example 8a 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.
  • Example 9a 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.
  • Example 10a 43 mg (73 // mol) of the silyl ether shown in Example 10a are reacted analogously to Example 1. After working up and purification, 17 mg (39 // mol, 54%) of the title compound is isolated as a colorless amorphous solid.
  • Example 10b 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.
  • ⁇ NMR (200MHz, CDC1 3 ): ⁇ 7.28 (5H), 5.52 (IH), 5.10 (IH), 4.82 (IH), 4.56 (IH), 3.93 (IH), 2.38 (2H), 1.76 (IH), 1.60-0.80 (32H) ppm.
  • Lithium aluminum hydride added and stirred at 23 ° C for one hour. Subsequently, 5 drops of methanol are then added dropwise while cooling with ice

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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

The disclosure relates to borneol derivatives of general formula (I) wherein: R1 represents a phenyl residue optionally substituted by halogen atoms, C¿1?-C4 alkyl groups, C1-C4 alkoxy groups, C1-C6 alkoxycarbonyl groups or C1-C8 acyloxy groups; R?2¿ stands for a hydrogen atom, a C¿1?-C4 alkyl group, substituted aryl, a C1-C6 alkoxycarbonyl group or a C1-C8 acyl group; R?3¿ stands for a hydrogen atom, a C¿1?-C4 alkyl group, a C1-C4 acyl group or a tri-C1-C4 alkylsilyl group; R?4 and R7¿ represent a hydrogen atom, a C¿1?-C4 alkyl residue or a phenyl residue optionally substituted by halogen atoms, C1-C4 alkyl group, C1-C9 alkoxy groups, C1-C4 alkoxycarbonyl groups or C1-C8 acyloxy groups; R?5 and R6¿ stand for a hydrogen atom, hydroxy group or a C¿1?-C8 acyloxy group, or together represent a carbon-carbon bond or oxygen atom; or R?4 and R5¿ and/or R?6 and R7¿ respectively stand together for a carbonyl group, a C¿1?-C4 alkylidene group or if required an oxirane group substituted by a C1-C3 alkyl group. Also disclosed are the salts of these derivatives with physiologically tolerable acids, their α-, β- or η-cyclodextrin clathrates and compounds of general formula (I) encapsulated in liposomes.

Description

Neue Borneole, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung New borneols, processes for their manufacture and their pharmaceutical use
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 influence tubulin polymerization or tubulin depolymerization.
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 Spindel apparat 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 or are in clinical trials. There are various classes of these mitotic poisons, which develop their cytotoxic effects either by inhibiting the polymerization of microtubules in the spindle apparatus (e.g. vinca alkaloids, colchicine) or by increasing the polymerization of tubulin independently of GTP and preventing depolymerization of Reach microtubules (e.g. Taxol, Taxotere). Mitotic poisons have a certain selectivity for tumor cells due to the physicochemical properties that have not yet been understood and the special features of neoplastic 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 Naturstoffe Taxol behindert zudem eine breitere klinische Testung.Vinca alkaloids are still of great importance in the combined chemotherapy of myeloid tumors. Taxanes have recently opened up important areas of application that were not accessible due to the cytostatics available to date, e.g. Ovarian cancer, malignant melanoma. However, the side effects of taxanes are comparable to those of other cytostatics (e.g. hair loss, sensory neuropathy). Multi-drug resistant tumor cells that overexpress the P-glycoprotein are 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.For this reason, natural substances and synthetic pharmaceuticals are tested that have a spectrum of activity that deviates from the previous mitotic poisons. An in vitro experimental setup enables the search for substances that do not influence the GTP-dependent polymerization of tubulin, but prevent the depolymerization of the microtubules formed. Substances with such an activity profile should influence the versatile functions of microtubules in extranuclear cell compartments less than the dynamics of the spindle apparatus during mitosis (meta / anaphase). Consequently, such compounds should show fewer side effects in vivo than 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. Among other things, it serves 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 accelerate the polymerization of tubulin (predominantly in the G2 phase) and the stabilize formed microtubule polymers. This mechanism differs significantly from those that have other structural classes that also influence phase-specific cell division. For example, substances from the group of vinca alkaloids (eg vincristine and vinblastine) but also colchicine inhibit the 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). Die neuen Borneolderivate sind gekennzeichnet durch die allgemeine Formel IIt has now been found that compounds of the formula I which are comparatively simple to prepare are able to inhibit the depolymerization of microtubules. On the basis of these properties, the compounds of the formula I are valuable pharmaceuticals which are in principle able to control the taxanes which are difficult to synthesize and are not yet available in sufficient quantities, such as e.g. To supplement or replace Taxol and Taxotere® in the therapy of malignant tumors (EP-A 253739). The new borneol derivatives are characterized by the general formula I
Figure imgf000004_0001
worin
Figure imgf000004_0001
wherein
R1 einen gegebenenfalls durch Halogenatome, Cι-C4-Alkylgruppen, C1-C4-R 1 a optionally by halogen atoms, -CC4-alkyl groups, C1-C4-
Alkoxygruppen, Ci-Cg-Alkoxycarbonylgruppen oder Ci-Cg-Alkoxy groups, Ci-Cg-alkoxycarbonyl groups or Ci-Cg-
Acyloxygruppen substituierter Phenylrest darstellt, R2 ein Wasserstoffatom, eine
Figure imgf000004_0002
substituiertes Aryl, eineCr Phenyl radical substituted by acyloxy groups, R 2 is a hydrogen atom, a
Figure imgf000004_0002
substituted aryl, aC r
Cß-Alkoxycarbonylgruppe oder eine Ci-Cg-Acylgruppe symbolisiert, R3 ein Wasserstoffatom, eine CrC4-Alkylgruppe, eine C1-C4-Acylgruppe oder eine
Figure imgf000004_0003
bedeutet und worin R4 und R7 ein Wasserstoffatom, einen CrC4-Alkylrest oder einen gegebenenfalls durchCβ-alkoxycarbonyl group or a Ci-Cg-acyl group symbolizes, R 3 represents a hydrogen atom, a C r C 4 alkyl group, a C 1 -C 4 acyl group or a
Figure imgf000004_0003
means and wherein R 4 and R 7 is a hydrogen atom, a C r C 4 alkyl radical or an optionally by
Halogenatome, C1-C4-Alkylgruppe, CrC9-Alkoxygruppen, C1-C4-Halogen atoms, C 1 -C 4 alkyl group, C r C 9 alkoxy groups, C 1 -C 4 -
Alkoxycarbonylgruppen oder C^Cg-Acyloxygruppen substituierterAlkoxycarbonylgruppen or C ^ Cg-Acyloxygruppen substituted
Phenylrest bedeuten und R5 und R6 ein Wasserstoffatom, eine Hydroxygruppe, oder eine C1-Cg-Acyloxygruppe darstellen oder gemeinsam eine Kohleπstoff-Kohlenstoffbindung oder einPhenyl radical and R 5 and R 6 represent a hydrogen atom, a hydroxy group, or a C 1 -Cg acyloxy group or together represent a carbon-carbon bond or a
Sauerstoffatom symbolisieren oder R4 und R5 und /oder R6 und R7 jeweils gemeinsam eine Carbonylgruppe, eine C1-C4-Symbolize oxygen atom or R 4 and R 5 and / or R 6 and R 7 each together represent a carbonyl group, a C 1 -C 4 -
Alkylidengruppe oder gewünschtenfalls durch eine C1-C3-Alkylgruppe substituierte Oxirangruppe bedeuten, sowie gegebenenfalls deren Salze mit physiologisch verträglichen Säuren, sowie deren α- , ß- oder γ-Cyclodextrinclathrateund die in Liposomen verkapselten Verbindungen der allgemeinen Formel I bedeuten. Die Erfindung betrifft die Diastereomeren und/oder Enantiomeren dieser Borneolderivate und auch deren Gemische.Alkylidene group or oxirane group substituted by a C 1 -C 3 alkyl group if desired, 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. The invention relates to the diastereomers and / or enantiomers of these borneol derivatives and also mixtures thereof.
Als Alkylgruppen dieser Borneolderivate sind gerad- oder verzweigtkettige Gruppen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Straight or branched-chain groups are to be considered as alkyl groups of these borneol derivatives, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-
Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl.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,As aryl radical of these compounds there are alicyclic, carbocyclic or heterocyclic radicals such as e.g. Phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl,
Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, die üblicherweise einfach oder mehrfach substituiert sein können, in Frage .Pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, which can usually be mono- or polysubstituted, into question.
Solche Substituenten sind beispielsweise Alkoxy-, Acyl- sowie Acyloxygruppen, wobeiSuch substituents are, for example, alkoxy, acyl and acyloxy groups, where
Methoxy-, Ethoxy- Propoxy- thaltenlsopropoxy-, t-Butyloxy-, Formyl, Acetyl,Methoxy-, ethoxy- propoxy- thaltenlsopropoxy-, t-butyloxy-, formyl, acetyl,
Propionyl-. und Isopropionylgruppen bevorzugt sind.Propionyl. and isopropionyl groups are preferred.
Freie Hydroxygruppen können funktionell abgewandelt sein, beispielsweise durchFree hydroxyl groups can be functionally modified, for example by
Veretherung oder Veresterung, wobei freie Hydroxygruppen bevorzugt sind.Etherification or esterification, free hydroxyl groups being preferred.
Als Ether- und Acylreste kommen die dem Fachmann bekannten Reste in Betracht.The radicals known to the person skilled in the art are suitable as ether and acyl radicals.
Bevorzugt sind leicht abspaltbare Etherreste, wie beispielsweise der Tetrahydropyranyl-,Easily removable ether residues, such as, for example, tetrahydropyranyl,
Tetrahydroruranyl-, tert.-Butyldimethylsilyl-, tert.-Butyldiphenylsilyl-, Tribenzylsilylrest.Tetrahydroruranyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl.
Als Acylreste kommen z.B. Acetyl, Propionyl, Butyryl, Benzoyl in Frage.As acyl residues e.g. Acetyl, propionyl, butyryl, benzoyl in question.
Halogen in den Definitionen für X bedeutet Fluor, Chlor, Brom und lod.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, as are known to the person skilled in the art for the formation of physiologically tolerable salts, are suitable for salt formation with the free bases.
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
Figure imgf000005_0001
in der R4, R5, R6 und R7 die oben genannten Bedeutungen haben und in R5 oder R6 enthaltene Hydroxylgruppen gegebenenfalls geschützt sind, mit einem Laαam der allgemeinen Formel lila oder einer Carboxylverbindung der allgemeinen Formel Illb,
Figure imgf000005_0001
in which R 4 , R 5 , R 6 and R 7 have the abovementioned meanings and hydroxyl groups contained in R 5 or R 6 are optionally protected, with a laαam of the general formula lilac or a carboxyl compound of the general formula Illb,
Figure imgf000005_0002
mit R1, R^ und R^ in der oben gennannten Bedeutung und X' in der Bedeutung OH, O- C(0)-CH(OR2)-CH(NHR2)-R1, Halogen oder CrC10-Alkyl haben kann und in lila bzw. Illb enthaltenen Hydroxylgruppen gegebenenfalls geschützt sind, verestert, gegebenfalls vorhandene Doppelbindungen oxidiert, geschützte Hydroxylgruppen freisetzt und in ein Derivat der allgemeinen Formel I überführt.
Figure imgf000005_0002
with R 1 , R ^ and R ^ in the abovementioned meaning and X 'in the meaning OH, O- C (0) -CH (OR 2 ) -CH (NHR 2 ) -R 1 , halogen or C r C 10 -Alkyl and may be protected in purple or Illb contained hydroxyl groups, esterified, any existing double bonds oxidized, protected hydroxyl groups released and converted into a derivative of general formula I.
Zur Veresterung der Alkohol funktion wird mit einer Base wie z.B. Metallhydriden (z.B. Natriumhydrid), Alkalialkoholaten (z.B. Natriummethanol at, Kalium-tert.-butanolat), Alkalihexamethyldisilazan (z.B. Natriumhexamethyldisilazan), 1,5-To esterify the alcohol function, a base such as e.g. 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-en (DBN), l,8-Diazabicyclo[5.4.0Jundec-7-en (DBU), Triethylamin, 4-(Dimethylamino)pyridin (DMAP), l,4-Diazabicydo[2.2.2]octan (DABCO) deprotoniert und mit Verbindungen der allgemeinen Formeln lila oder Illb 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 Carbonsaurederivat, Tetrahydroruran als Solvens bei Temperaturen von -40°C bis +25°C.Diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0Jundec-7-ene (DBU), triethylamine, 4- (dimethylamino) pyridine (DMAP), 1,4-diazabicydo [ 2.2.2] octane (DABCO) deprotonated and with compounds of the general formulas lilac or Illb or with other suitable carboxylic acid derivatives such as, for example Acid amides, acid anhydrides in an inert solvent such as e.g. Dichloromethane, diethyl ether, tetrahydrofuran at -70 ° C to + 50 ° C implemented. The reaction with sodium hexamethyldisilazane as the base, a cyclic acid amide as the carboxylic acid derivative, tetrahydroruran as the solvent at temperatures from -40 ° C. to + 25 ° C. is preferred.
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 R 5 and R 6 together represent a bond or R 4 and R 5 and / or. R 6 and R 7 together represent an alkylidene group, the functionalization of the olefinic double bond can be carried out by the methods known to the person skilled in the art. For example, hydrogen can be added, for example by cat. Hydrogenation, hydroxyl groups can be introduced by water addition (hydroboration, oxymercuration) or by 1,2-bishydroxylation, for example 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 a hydroxyl group. A carbonyl group produced in this way can, for example, be reduced, alkylated or used as a carbonyl component in a Wittig reaction to build up modified = CHR 6 groups.
Falls R4 und R^ und/oder R*> 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-Toluolsulf onsäure oder Lewissäuren wie beispielsweise Bortrifluoridetherat, Titantetraisopropoxid, Cerammoniumnitrat entweder in inerten oder als Nucleophil fungierenden Lösungsmitteln bei -70°C bis +50°C gespalten werden. Biologische Wirkungen und Anwendungsbereiche der neuen Borneolderivate:If R 4 and R ^ and / or R *> and R 7 together represent an optionally substituted oxirane group, the epoxide can be formed 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 For example, hydrogen chloride, para-toluenesulfonic acid or Lewis acids, such as, for example, boron trifluoride etherate, titanium tetraisopropoxide, cerium ammonium nitrate, can be cleaved either in inert solvents or solvents which function as a nucleophile at -70 ° C. to + 50 ° C. Biological effects and areas of application of the new borneol derivatives:
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. Als Beispiele seien genannt die Kombination mit O Platinkomplexen wie z.B. Cisplatin, Carboplatin, O interkalierenden Substanzen z.B. aus der Klasse der Anthracycline wie z.B.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 indicated therapeutically, such as e.g. 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 classes of substances which can be used in tumor therapy. Examples include the combination with O platinum complexes such as Cisplatin, carboplatin, O intercalating substances e.g. from the class of anthracyclines such as
Doxorubicin oder aus der Klasse der Antrapyrazole wie z.B. CI-941, O 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,Doxorubicin or from the class of antrapyrazoles such as e.g. CI-941, O with substances interacting with tubulin e.g. from the class of vinca alkaloids such as Vincristine, vinblastine or from the taxane class such as Taxol,
Taxotere oder aus der Klasse der Makrolide wie z.B. Rhizoxin oder andereTaxotere or from the macrolide class such as Rhizoxin or others
Verbindungen wie z.B. Colchicin, Combretastatin A-4, O DNA Topoisomeraseinhibitoren wie z.B. Camptothecin, Etoposid, Topotecan,Connections such as Colchicine, combretastatin A-4, O DNA topoisomerase inhibitors such as e.g. Camptothecin, etoposide, topotecan,
Teniposid, O Folat- oder Pyrimidin-Antimetaboliten wie z.B. Lometrexol, Gemcitubin, O DNA alkylierenden Verbindungen wie z.B. Adozelesin, Dystamycin A, O Inhibitoren von Wachstums faktoren (z.B. von PDGF, EGF, TGFß, EGF) wie z.B.Teniposide, O folate or pyrimidine antimetabolites such as e.g. Lometrexol, gemcitubin, O DNA alkylating compounds such as e.g. Adozelesin, dystamycin A, O inhibitors of growth factors (e.g. of PDGF, EGF, TGFß, EGF) such as e.g.
Somatostatin, Suramin, Bombesin-Antagonisten, O Inhibitoren der Protein Tyrosin Kinase oder der Protein Kinasen A oder C wie z.B.Somatostatin, suramin, bombesin antagonists, O inhibitors of protein tyrosine kinase or protein kinases A or C such as e.g.
Erbstatin, Genistein, Staurosporin, Ilmofosin, 8-Cl-cAMP, O 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 derErbstatin, Genistein, Staurosporin, Ilmofosin, 8-Cl-cAMP, O anti-hormones from the class of the antigestagens such as e.g. Mifepristone, onapristone or from the class of anti-estrogens such as Tamoxifen or from the class of
Antiandrogene wie z.B. Cyproteronacetat, O Metastasen inhibierenden Verbindungen z.B. aus der Klasse der Eicosanoide wie z.B. PGI2, PGEj, 6-Oxo-PGEi sowie deren stabiler Derivate (z.B. Iloprost,Antiandrogens such as, for example, cyproterone acetate, O metastasis-inhibiting compounds, for example from the class of the eicosanoids, such as PGI 2 , PGEj, 6-oxo-PGEi and their stable derivatives (for example iloprost,
Cicaprost, Beraprost), O Inhibitoren des transmembranären Ca2+-Influx wie z.B. Verapamil, Galopamil,Cicaprost, beraprost), O inhibitors of the transmembrane Ca 2+ influx such as verapamil, galopamil,
Flunarizin, Diltiazem, Nifedipin, Nimodipin, O Neuroleptika wie z.B. Chlorpromazin, Trifuoperazin, Thioridazin, Peφhenazin, O Lokalanästhetika wie z.B. Carbanilat-Ca7, Cinchocain, Carbanilat-Ca3, Articain,Flunarizine, diltiazem, nifedipine, nimodipine, neuroleptics such as e.g. Chlorpromazin, Trifuoperazin, Thioridazin, Peφhenazin, O local anesthetics like e.g. Carbanilate-Ca7, cinchocaine, carbanilate-Ca3, articaine,
Carbanilat, Lidocain. O die Angiogenese inhibierenden Substanzen wie z.B. anti-VEGF-Antikörpern,Carbanilate, lidocaine. O substances that inhibit angiogenesis, e.g. anti-VEGF antibodies,
Endostatin B, Interferon α, AGM 1470, O Inhibitoren der Zeilproliferation bei Psoriasis, Kaposisarcom, Neuroblastom.Endostatin B, interferon α, AGM 1470, O 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. 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 invention also relates to pharmaceuticals based on the pharmaceutically acceptable, i.e. in the doses used, non-toxic borneol derivatives of the general formula I, if appropriate together with the customary auxiliaries and carriers. The compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragées, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
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 commonly used in galenics, e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifying agents, preservatives and flavoring agents for flavor correction (for example essential oils) become.
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 contain at least one compound according to the invention as active ingredient. One dose unit contains about 0.1-100 mg of active ingredient (s). The dosage of the compounds according to the invention in humans is about 0.1-1000 mg per day.
Die nachfolgenden Ausfuhrungsbeispiele dienen zur weiteren Erläuterung des erfindungsgemäßen Verfahrens. BEISPIEL 1The following exemplary embodiments serve to further explain the method according to the invention. EXAMPLE 1
(lR,2S,2'R^'S,4S)-3'-tert-Butoxycarbonylamino-2'-hydroxy-3'-phenyl- propionsäure-l,7,7-trimethyl-5-methylen-bicyclo[2.2.1]hept-2-yIester(IR, 2S, 2'R ^ 'S, 4S) -3'-tert-butoxycarbonylamino-2'-hydroxy-3'-phenyl-propionic acid-1, 7,7-trimethyl-5-methylene-bicyclo [2.2. 1] hept-2-yester
Unter Argonatmosphäre werden 42 mg (0,071 mmol) des nach Beispiel la dargestellten Silylethers in 3 ml wasserfreiem Tetrahydrofuran über Molsieb (3 Ä) 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; R, = 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, Rt = 0,24). Isoliert werden 10 mg (0,023 mmol, 33%) der Titelverbindung als gelbliches Öl.Under an argon atmosphere, 42 mg (0.071 mmol) of the silyl ether prepared according to Example la in 3 ml of anhydrous tetrahydrofuran are introduced through a 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, = 0.45), and the reaction is mixed with saturated ammonium chloride solution. 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 t = 0.24). 10 mg (0.023 mmol, 33%) of the title compound are isolated as a yellowish oil.
Η-NMR (400 MHz, CDClj): δ = 7,25-7,38 (5H), 5,41 (IH), 5,18 (IH), 5,05 (IH), 4,83 (IH), 4,69 (IH), 4,49 (IH), 3,16 (IH), 2,56 (IH), 2,48 (IH), 2,19 (IH), 2,01 (IH), 1,40 (9H), 1,26 (IH), 0,94 (3H), 0,90 (3H), 0,88 (3H) ppm.Η NMR (400 MHz, CDClj): δ = 7.25-7.38 (5H), 5.41 (IH), 5.18 (IH), 5.05 (IH), 4.83 (IH) , 4.69 (IH), 4.49 (IH), 3.16 (IH), 2.56 (IH), 2.48 (IH), 2.19 (IH), 2.01 (IH), 1.40 (9H), 1.26 (IH), 0.94 (3H), 0.90 (3H), 0.88 (3H) ppm.
BEISPIEL laEXAMPLE la
(lR,2S,2,R,3'S,4S)-3,-tert-Butoxycarbonylamino-3'-phenyl-2'-triiso- propy.sUyloxy-3' -propionsäure-l,7,7-trimethyI-5-methylen-bicycIo[2.2.1]hept-2- ylester(lR, 2S, 2 , R, 3'S, 4S) -3 , -tert-butoxycarbonylamino-3'-phenyl-2'-triisopropy.sUyloxy-3'-propionic acid-l, 7,7-trimethyI-5- methylene bicyclo [2.2.1] hept-2-yl ester
Es werden 33 mg (0,2 mmol) des nach Beispiel lb dargestellten Alkohols in 3 ml wasserfreiem Tetrahydrofuran unter Argon vorgelegt und 100,7 mg (0,24 mmol) (3R,4S)-l-[(l,l-dimethylethoxy)carbonyI3-3-triisopropylsilyloxy-4-phenyl-2-azetidinon im Argongegenstrom dazugegeben. Zu der auf -35CC 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; Rt = 0.62) erfolgt der Abbruch der Reaktion durch Zugabe von gesättigter Ammoniumchlorid-Lδsung. Anschließend wird viermal mit Methyl-t- butylether extrahiert, über Magnesiumsulfat getrocknet, das Lösungsmittel am Rotationsverdampfer abdestiliert und das Rohprodukt flash-chromatographisch gereinigt. Isoliert werden 69 mg (0.12 mmol; 60%) der Titelverbindung als farbloses Öl Η-NMR (400 MHz, CDC1,): δ = 7,20-7,34 (5H), 5,59 (IH), 5,07 (IH), 5,01 (IH), 4,81 (IH), 4,63 (IH), 4,61 (IH), 2,57 (IH), 2,44 (IH), 2,17 (IH), 1,96 (IH), 1,40 (9H), 1,10 (IH), 0,94 (21H), 0,90 (IH), 0,88 (IH), 0,86 (IH) ppm. BEISPIEL lb33 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) -l - [(l, l-dimethylethoxy ) carbonyI3-3-triisopropylsilyloxy-4-phenyl-2-azetidinone added in counter argon flow. 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 t = 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 flash chromatography. 69 mg (0.12 mmol; 60%) of the title compound are isolated as a colorless oil NMR-NMR (400 MHz, CDC1,): δ = 7.20-7.34 (5H), 5.59 (IH), 5.07 (IH), 5.01 (IH), 4.81 (IH), 4.63 (IH), 4.61 (IH), 2.57 (IH), 2.44 (IH), 2.17 ( IH), 1.96 (IH), 1.40 (9H), 1.10 (IH), 0.94 (21H), 0.90 (IH), 0.88 (IH), 0.86 (IH ) ppm. EXAMPLE lb
(lR,2S,4S)-l,7,7-TrimethyI-S-methyIen-bicycIo[2.2.1]heptan-2-ol(IR, 2S, 4S) -l, 7,7-trimethyl-S-methylene-bicyclo [2.2.1] heptan-2-ol
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/I Titantetrachlorid in Dichlormethan dazu. Es bildet sich eine dunkelbraune Lösung, zu der nach 20 Minuten 280 mg (1,3 mmol) des nach Beispiel lc 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-Lδsung 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 Η-NMR (400 MHz, CDC1,): δ = 4,80 (IH), 4,61 (IH), 4,07 (IH), 2,55 (IH), 2,43 (IH), 2,13 (IH), 1,91 (IH), 1,10 (IH), 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 280 mg (1.3 mmol) of the ketone shown in Example 1c, dissolved in 3 ml of anhydrous tetrahydrofuran, is 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 NMR-NMR (400 MHz, CDC1,): δ = 4.80 (IH), 4.61 (IH), 4.07 (IH ), 2.55 (IH), 2.43 (IH), 2.13 (IH), 1.91 (IH), 1.10 (IH), 0.89 (3H), 0.87 (3H) , 0.85 (3H) ppm.
BEISPIEL lcEXAMPLE lc
(IR, 2S,4R) Essiggsäurel,7,7-trimethyI-5-oxo-bicyclo[2.2.1]hept-2-yIester(IR, 2S, 4R) acetic acid, 7,7-trimethyl-5-oxobicyclo [2.2.1] hept-2-yIester
Zu einer eisgekühlten Lösung von 4,85g (24,7 mmol) des nach Beispiel ld dargestellten Acetates in 20 ml Eisessig und 9 ml Acetanhydrid werden 7,0g (70 mmol) CrO, 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 Reaktionverlauf wird mittels DC-Kontrolle verfolgt (Methyl-t- butylether/Petrolether 1:4; Rf =0,47). Der Reaktionsansatz wird auf ca. 0,5 1 Wasser gegeben und fünfmal mit Methyl-t-butylether extrahiert. Zur Phasentrennung wird über Celite filtriert. Die vereinigten organischen Phasen werden mit gesättigter Na2CO3- Lδsung gewaschen und über Magnesiumsuifat 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. Η-NMR (400 MHz,CDCl3): Ö = 5,07 (IH), 2,63 (IH), 2,55 (IH), 2,19 (IH), 2,07 (3H), 2,00 (IH), 1,32 (IH), 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 CrO, 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 Na 2 CO 3 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. Η NMR (400 MHz, CDCl 3 ): Ö = 5.07 (IH), 2.63 (IH), 2.55 (IH), 2.19 (IH), 2.07 (3H), 2, 00 (IH), 1.32 (IH), 1.03 (3H), 1.01 (3H), 0.95 (3H) ppm.
BEISPIEL ldEXAMPLE ld
(IR, 2S,4R)-Essigsäurel,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylester(IR, 2S, 4R) -acetic acid, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl ester
2,991g (19 mmol) (lR)-(+)-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.2.991 g (19 mmol) (IR) - (+) - 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.
Η-NMR (400 MHz,CDCl3): δ = 4,87 (IH), 2,35 (IH), 2,06 (3H), 1,93 (IH), 1,74 (IH), 1,67 (IH), 1,19-1,34 (2H), 0,96 (IH), 0,90 (3H), 0,87 (3H), 0,83 (3H) ppm.Η NMR (400 MHz, CDCl 3 ): δ = 4.87 (IH), 2.35 (IH), 2.06 (3H), 1.93 (IH), 1.74 (IH), 1, 67 (IH), 1.19-1.34 (2H), 0.96 (IH), 0.90 (3H), 0.87 (3H), 0.83 (3H) ppm.
BEISPIEL 2EXAMPLE 2
(lR,2S,2,R,3'S,4R,5R)-3'-tert-Butoxycarbonylamino-2'-hydroxy-3'-phenyl- propionsäure-l,7,7-trimethyI-S-oxa-spiro[2.4]bicycIo[2.2.1]hept-2-ylester(lR, 2S, 2 , R, 3'S, 4R, 5R) -3'-tert-butoxycarbonylamino-2'-hydroxy-3'-phenyl-propionic acid-l, 7,7-trimethyI-S-oxa-spiro [2.4 ] bicyclo [2.2.1] hept-2-yl ester
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 Öl17 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
Η-NMR (400 MHz, CDC13): δ = 5,25-5,40 (5H), 5,38 (IH), 5,22 (IH), 4,97 (IH), 4,53 (IH), 3,16 (IH), 2,91 (IH), 2,68 (IH), 2,48 (IH), 2,32 (IH), 1,69 (IH), 1,43 (IH), 1,40 (9H), 1,32 (IH), 1,14 (3H), 0,97 (3H), 0,95 (3H) ppm.Η NMR (400 MHz, CDC1 3 ): δ = 5.25-5.40 (5H), 5.38 (IH), 5.22 (IH), 4.97 (IH), 4.53 (IH ), 3.16 (IH), 2.91 (IH), 2.68 (IH), 2.48 (IH), 2.32 (IH), 1.69 (IH), 1.43 (IH) , 1.40 (9H), 1.32 (IH), 1.14 (3H), 0.97 (3H), 0.95 (3H) ppm.
BEISPIEL 2aEXAMPLE 2a
(lR,2S,2,R,3'S,4R,5R)-3'-tert-Butoxycarbonylamino-3'-phenyl-2-triisopropyIsilyl- oxy-3'-propionsäure-l,7,7-triιnethyl-5-oxa-spiro[2.4]bicyc!o[2.2.1]hept-2-ylester(1R, 2S, 2 , R, 3'S, 4R, 5R) -3'-tert-butoxycarbonylamino-3'-phenyl-2-triisopropyisilyloxy-3'-propionic acid-l, 7,7-tri-methyl-5-oxa -spiro [2.4] bicyc! o [2.2.1] hept-2-yl ester
Von dem nach Beispiel la 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.52 mg (0.09 mmol) of 4 ml of dichloromethane are initially introduced from the silyl ether prepared according to Example la, 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.
Η-NMR (400 MHz, CDCI3): δ = 7,20-7,33 (5H), 5,55 (IH), 5,12 (IH), 4,92 (IH), 4,64 (IH), 2,81 (IH), 2,66 (IH), 2,46 (IH), 2,27 (IH), 1,65 (IH), 1,40 (11H), 1,12 (s;3H), 0,94 (3H), 0,92 (3H), 0,88 (21H) ppm. BEISPIEL 3Η NMR (400 MHz, CDCI 3 ): δ = 7.20-7.33 (5H), 5.55 (IH), 5.12 (IH), 4.92 (IH), 4.64 (IH ), 2.81 (IH), 2.66 (IH), 2.46 (IH), 2.27 (IH), 1.65 (IH), 1.40 (11H), 1.12 (s; 3H), 0.94 (3H), 0.92 (3H), 0.88 (21H) ppm. EXAMPLE 3
(lR,2S,2,R^,S,4R,SR)-3'-tert-Butoxycarbonylamino-2'-hydroxy-3,-phenyl- propionsäure-5-hydroxy-l,7,7-trimethyI-6-oxo-5-phenyI-bicyclo[2.2.1]hept-2- ylester(1R, 2S, 2 , R ^ , S, 4R, SR) -3'-tert-butoxycarbonylamino-2'-hydroxy-3 , -phenyl-propionic acid-5-hydroxy-l, 7,7-trimethyl-6- oxo-5-phenyl-bicyclo [2.2.1] hept-2-yl ester
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.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.
Η-NMR (400MHz, CDC13): δ = 7,20-7,45 (10H), 5,21 (IH), 5,13 (IH), 4,74 (IH) 4,34 (IH), 3,03 (IH) 2,70 (IH), 2,63 (IH), 2,45 (IH), 1,37 (8H), 1,35 (IH), 1,22 (s;3H), 1,13 (3H), 1,02 (3H) ppm.Η NMR (400MHz, CDC1 3 ): δ = 7.20-7.45 (10H), 5.21 (IH), 5.13 (IH), 4.74 (IH) 4.34 (IH), 3.03 (IH) 2.70 (IH), 2.63 (IH), 2.45 (IH), 1.37 (8H), 1.35 (IH), 1.22 (s; 3H), 1.13 (3H), 1.02 (3H) ppm.
BEISPIEL 3aEXAMPLE 3a
(lR,2S,2'R,3,S,4R,5R)-3'-tert-Butoxycarbonylamino-3'-phenyI-2~tri-iso- propylsiIyloxy-propionsäure-5-hydroxy-l,7,7-trimethyl-6-oxo-5-phenyl- bicyclo[2.2.1]hept-2-ylester(1R, 2S, 2'R, 3 , S, 4R, 5R) -3'-tert-butoxycarbonylamino-3'-phenyl-2 ~ tri-isopropylsiyloxy-propionic acid-5-hydroxy-l, 7,7- trimethyl-6-oxo-5-phenyl-bicyclo [2.2.1] hept-2-yl ester
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 Os04 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 Öl0.1 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. 24 mg (0.216 mmol) trimethylamine N-oxide (dihydrate) and 24 μl of a 4% solution of Os0 4 in water (»1 mg OsO 4 ) are then 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
Η-NMR (400MHz,CDCl3): δ = 7,15-7,50 (10H), 5,28 (2H), 4,60 (IH), 4,43 (IH), 2,66 (IH), 2,62 (IH), 2,41 (IH), 1,34 (10H), 1,22 (3H), 1,13 (3H), 1,05 (3H), 0,90 (21H) ppm.Η NMR (400MHz, CDCl 3 ): δ = 7.15-7.50 (10H), 5.28 (2H), 4.60 (IH), 4.43 (IH), 2.66 (IH) , 2.62 (IH), 2.41 (IH), 1.34 (10H), 1.22 (3H), 1.13 (3H), 1.05 (3H), 0.90 (21H) ppm .
BEISPIEL 3bEXAMPLE 3b
(lR,2S,2,R,3'S,4S)-3,-tert-Butoxycarbonylamino-3'-phenyI-2-triisopropy!silyIoxy- propionsäure-l,7,7-trimethyI-5-phenyl-bicycIo[2.2.1]hept-5-en-2-ylester(IR, 2S, 2 , R, 3'S, 4S) -3 , tert-butoxycarbonylamino-3'-phenyI-2-triisopropy! silyIoxypropionic acid-l, 7,7-trimethyI-5-phenyl-bicyclo [2.2. 1] hept-5-en-2-yl ester
45 mg (0,2 mmol) des nach Beispiel 3c dargestellten Alkohols werden in Analogie zu Beispiel la umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 100 mg (0,15 mmol, 75%) der Titelverbindung als farbloses Öl.45 mg (0.2 mmol) of the alcohol shown in Example 3c are reacted analogously to Example la. After working up and purification, 100 mg (0.15 mmol, 75%) of the title compound are isolated as a colorless oil.
Η-NMR (400MHz, CDC13): δ = 7,12-7,45 (10H), 5,82 (IH), 5,62 (IH), 5,33 (IH), 5,07 (IH), 4,53 (IH), 4,30 (IH), 4,05 (IH), 1,45 (9H), 1,06 (3H), 0,97 (IH), 0,92 (IH), 0,90 (3H), 0,83 (21H) ppm. BEISPIEL 3cΗ NMR (400MHz, CDC1 3 ): δ = 7.12-7.45 (10H), 5.82 (IH), 5.62 (IH), 5.33 (IH), 5.07 (IH) , 4.53 (IH), 4.30 (IH), 4.05 (IH), 1.45 (9H), 1.06 (3H), 0.97 (IH), 0.92 (IH), 0.90 (3H), 0.83 (21H) ppm. EXAMPLE 3c
(lR,2S,4S)-l,7,7-Trimethy!-5-phenyI-bicycIo[2.2.1]hept-5-en-2-ol(IR, 2S, 4S) -l, 7,7-trimethyl! -5-phenyl-bicyclo [2.2.1] hept-5-en-2-ol
211 mg (0,93 mmol) des nach Beispiel 3d dargestellten Gemisches werden in 5 ml wasserfreiem Et20 unter Argonatmosphäre gelöst und mit 394 mg (= 0,35 ml, 2,78 mmol) einer 50%igen Lösung von BF3 in Et20 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-Lδsung 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) (lS,2R,4S)-2-Hydroxy-l,7,7-trimethyl-bicyclo[2.2.1]heptan-5-on jeweils als farblose Kristalle.211 mg (0.93 mmol) of the mixture shown in Example 3d are dissolved in 5 ml of anhydrous Et 2 0 under an argon atmosphere and with 394 mg (= 0.35 ml, 2.78 mmol) of a 50% solution of BF 3 in Et 2 0 added. 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) (lS, 2R, 4S) -2-hydroxy-l, 7,7-trimethyl-bicyclo [2.2.1] are isolated heptan-5-one each as colorless crystals.
Η-NMR (400MHZ, CDC13): δ = 7,35 (5H), 6,01 (IH), 4,25 (IH), 2,80 (IH), 2,60 (IH), 1,20 (3H), 0,98 (IH), 0,90 (3H), 0,88 (3H) ppm.Η NMR (400MHZ, CDC1 3 ): δ = 7.35 (5H), 6.01 (IH), 4.25 (IH), 2.80 (IH), 2.60 (IH), 1.20 (3H), 0.98 (IH), 0.90 (3H), 0.88 (3H) ppm.
BEISPIEL 3dEXAMPLE 3d
(lR,2S,4R,5RS)-l,7,7-TrimethyI-5-phenyl-bicyclo[2.2.1]heptan-2,5-diol(IR, 2S, 4R, 5RS) -1,7,7-trimethyl-5-phenyl-bicyclo [2.2.1] heptane-2,5-diol
Unter Argon werden 330 mg (1,57 mmol) des nach Beispiel lc 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 (lS,2R,4S)-2-Hydroxy-l,7,7-trimethyl- bicyclo[2.2.1]heptan-5-on, welches ohne Trennung weiter umgesetzt wird. Η-NMR (400MHZ, CDC13): δ = 6,25-6,51 (5H), 4,23 (IH), 4,03 (IH), 2,62 (IH), 2,56 (IH), 2,50 (IH), 2,32 (IH), 2,27 (IH), 2,23 (IH), 2,14 (IH), 2,07 (IH), 1,90 (IH), 1,81 (IH), 1,30 (IH), 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 (IS, 2R, 4S) -2-hydroxy-l, 7,7-trimethyl-bicyclo [2.2.1] heptan-5-one are isolated , which is implemented without separation. Η NMR (400MHZ, CDC1 3 ): δ = 6.25-6.51 (5H), 4.23 (IH), 4.03 (IH), 2.62 (IH), 2.56 (IH) , 2.50 (IH), 2.32 (IH), 2.27 (IH), 2.23 (IH), 2.14 (IH), 2.07 (IH), 1.90 (IH), 1.81 (IH), 1.30 (IH), 1.02 (3H), 0.96 (6H), 0.94 (3H), 0.93 (3H), 0.87 (3H) ppm.
BEISPIEL 4EXAMPLE 4
(lR,2S,2'Rr3'S,4S)-3'-tert-Butoxycarbonylamino-2'-hydroxy-3-phenyl- propionsäure-l,7,7-trimethyl-5-phenyI-bicyclo[2.2.1]hept-5-en-2-ylester(lR, 2S, 2'R r 3'S, 4S) -3'-tert-butoxycarbonylamino-2'-hydroxy-3-phenylpropionic acid-l, 7,7-trimethyl-5-phenyI-bicyclo [2.2.1] hept-5-en-2-yl ester
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. Η-NMR (400MHz, CDC13): δ = 6,95-7,57 (10H), 6,12 (1H)5,95 (IH), 5,21 (IH), 4,99 (IH), 4,42 (IH), 3,02 (IH), 2,88 (IH), 2,54 (IH), 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. Η-NMR (400MHz, CDC1 3 ): δ = 6.95-7.57 (10H), 6.12 (1H) 5.95 (IH), 5.21 (IH), 4.99 (IH), 4.42 (IH), 3.02 (IH), 2.88 (IH), 2.54 (IH), 1.45 (9H), 1.17 (3H), 1.02 (3H), 0 , 94 (3H) ppm.
BEISPIEL 4aEXAMPLE 4a
(lR,2S,2,R,3'S,4S)-3'-tert-Butoxycarbonylamino-3,-phenyl-2'-trüsopropylsiIyl- oxy-propionsäure-l,7,7-trimethyI-5-phenyl-bicyclo[2.2.1]hept-5-en-2-ylester(IR, 2S, 2 , R, 3'S, 4S) -3'-tert-Butoxycarbonylamino-3 , -phenyl-2'-trüsopropylsiIyl-oxy-propionic acid-l, 7,7-trimethyl-5-phenyl-bicyclo [2.2 .1] hept-5-en-2-yl ester
45 mg (0,2 mmol) des nach Beispiel 3c dargestellten Alkohols werden in Analogie zu Beispiel la umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 100 mg (0,15 mmol, 75%) der Titelverbindung als farbloses Öl.45 mg (0.2 mmol) of the alcohol shown in Example 3c are reacted analogously to Example la. After working up and purification, 100 mg (0.15 mmol, 75%) of the title compound are isolated as a colorless oil.
Η-NMR (400MHz, CDCI3): δ = 7,12-7,45 (10H), 5,82 (IH), 5,62 (IH), 5,33 (IH), 5,07 (IH), 4,53 (IH), 4,30 (IH), 4,05 (IH), 1,45 (9H), 1,06 (3H), 0,97 (IH), 0,92 (s;lH), 0,90 (3H), 0,83 (21H) ppm.Η NMR (400MHz, CDCI 3 ): δ = 7.12-7.45 (10H), 5.82 (IH), 5.62 (IH), 5.33 (IH), 5.07 (IH) , 4.53 (IH), 4.30 (IH), 4.05 (IH), 1.45 (9H), 1.06 (3H), 0.97 (IH), 0.92 (s; lH ), 0.90 (3H), 0.83 (21H) ppm.
BEISPIEL 5EXAMPLE 5
(lR,2S,2'R,3,S,4S,5RS)-3,-tert-ButoxycarbonyIamino-2'-hydroxy-3'-phenyI. propionsäure-l,7,7-trimethyl-6-oxo-5-phenyl-bicycIo[2.2.1]hept-2-ylester(IR, 2S, 2'R, 3 , S, 4S, 5RS) -3 , tert-butoxycarbonylamino-2'-hydroxy-3'-phenyl. propionic acid-l, 7,7-trimethyl-6-oxo-5-phenyl-bicyclo [2.2.1] hept-2-yl ester
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.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.
1H-NMR (400MHz, CDC13): δ = 7,17-7,55 (5H), 5,32 (2H), 5,16 (3H), 4,87 (IH), 4,51 (IH), 4,43 (IH), 3,96 (IH), 3,55 (IH), 3,20 (IH), 3,12 (IH), 2,89 (2H), 2,57 (IH), 2,35 (IH), 1,56 (2H), 1,39 (9H), 1,35 (9H), 1,06 (6H), 1,04 (6H), 0,99 (6H) ppm.1H-NMR (400MHz, CDC1 3 ): δ = 7.17-7.55 (5H), 5.32 (2H), 5.16 (3H), 4.87 (IH), 4.51 (IH) , 4.43 (IH), 3.96 (IH), 3.55 (IH), 3.20 (IH), 3.12 (IH), 2.89 (2H), 2.57 (IH), 2.35 (IH), 1.56 (2H), 1.39 (9H), 1.35 (9H), 1.06 (6H), 1.04 (6H), 0.99 (6H) ppm.
BEISPIEL 5aEXAMPLE 5a
(lR,2S,2,R^,S,4S,5S)-3,-tert-ButoxycarbonyIamino-3'-pheny!-2'-triisopropyI- siIyloxy-propionsäure-l,7,7-trimethyl-6-oxo-5-phenyl-bicyclo[2.2.1]hept-2-yIester(lR, 2S, 2 , R ^ , S, 4S, 5S) -3 , -tert-butoxycarbonylamino-3'-pheny! -2'-triisopropyl-siIyloxy-propionic acid-l, 7,7-trimethyl-6-oxo -5-phenyl-bicyclo [2.2.1] hept-2-yester
12 mg (0,08 mmol) des nach Beispiel 5b dargestellten Alkohols werden in Analogie zu12 mg (0.08 mmol) of the alcohol shown in Example 5b are analogous to
Beispiel la umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 24 mg (0,036 mmol; 45%) der Titelverbindung als gelbes Öl.Example la implemented. After working up and purification, 24 mg (0.036 mmol; 45%) of the title compound are isolated as a yellow oil.
Η-NMR (400MHz, CDC13): δ = 7,18-7,40 (10H), 5,37 (2H), 4,87 (IH), 4,52 (IH), 3,97Η NMR (400MHz, CDC1 3 ): δ = 7.18-7.40 (10H), 5.37 (2H), 4.87 (IH), 4.52 (IH), 3.97
(IH), 2,52 (IH), 2,28 (IH), 1,37 (10H), 1,06 (3H), 1,04 (3H), 0,99 (3H), 0,91 (21H) ppm. BEISPIEL 5b (lR,2S,4S,5S)-2-Hydroxy-l,7,7-trimethyI-5-phenyI-bicycIo[2.2.1]heptan-6-on(IH), 2.52 (IH), 2.28 (IH), 1.37 (10H), 1.06 (3H), 1.04 (3H), 0.99 (3H), 0.91 ( 21H) ppm. EXAMPLE 5b (IR, 2S, 4S, 5S) -2-hydroxy-l, 7,7-trimethyI-5-phenyI-bicyclo [2.2.1] heptan-6-one
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.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.
Η-NMR (400MHz, CDC13): δ = 7,19-7,35 (5H), 4,30 (IH), 3,91 (IH), 2,43 (IH), 2,27 (IH), 1,45 (IH), 1,08 (3H), 1,06 (3H), 1,02 (3H) ppm.Η NMR (400MHz, CDC1 3 ): δ = 7.19-7.35 (5H), 4.30 (IH), 3.91 (IH), 2.43 (IH), 2.27 (IH) , 1.45 (IH), 1.08 (3H), 1.06 (3H), 1.02 (3H) ppm.
BEISPIEL 6EXAMPLE 6
(lR^S^'R^'S^RJ-SMert-Butoxycarbonylamino^'-hydroxy-S'-phenyl- propionsäure-l,7,7-trimethyI-bicyclo[2.2.1]hept-2-ylester(IR ^ S ^ 'R ^' S ^ RJ-SMert-Butoxycarbonylamino ^ '- hydroxy-S'-phenyl-propionic acid-l, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl ester
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.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.
Η-NMR (300MHz, CDC13): δ =.7,22-7,48 (5H), 5,43 (IH), 5,27 (IH), 4,95 (IH), 4,51 (IH), 3,18 (IH), 2,38 (IH), 1,99 (IH), 1,25-1,85 (13H), 0,80-1,15 (10H) ppm.Η NMR (300 MHz, CDC1 3 ): δ = .7.22-7.48 (5H), 5.43 (IH), 5.27 (IH), 4.95 (IH), 4.51 (IH ), 3.18 (IH), 2.38 (IH), 1.99 (IH), 1.25-1.85 (13H), 0.80-1.15 (10H) ppm.
BEISPIEL 6aEXAMPLE 6a
(lR,2S,2,R,3,S,4R)-3'-tert-ButoxycarbonyIamino-3'-phenyl-2'-triiso- propyIsilyIoxy-3,-propionsäure-l,7,7-trimethyI-bicyclo[2.2.1]hept-2-yIester(lR, 2S, 2 , R, 3 , S, 4R) -3'-tert-butoxycarbonylamino-3'-phenyl-2'-triisopropyIsilyIoxy-3 , -propionic acid-l, 7,7-trimethyI-bicyclo [ 2.2.1] hept-2-ester
100 mg (0,65 mmol) (lR)-(+)-Bomeol werden in Analogie zu Beispiel la umgesetzt. Nach Aufarbeitung isoliert man 427 mg der Titelverbindung als Rohprodukt, das ohne Reinigung weiter umgesetzt wird.100 mg (0.65 mmol) (IR) - (+) - Bomeol are reacted in analogy to example la. After working up, 427 mg of the title compound is isolated as a crude product which is reacted further without purification.
BEISPIEL 7EXAMPLE 7
(lR,2S,2'R^,S,4R)-3,-Benzoylamino-2'.hydroxy-3'-phenyI-propionsäure-l,7,7- trimethyl-bicyclo [2.2.1] hept-2-ylester(lR, 2S, 2'R ^ , S, 4R) -3 , -Benzoylamino-2'.hydroxy-3'-phenyI-propionic acid-l, 7,7-trimethyl-bicyclo [2.2.1] hept-2- ylester
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. lH-NMR (300MHz, CDC13): δ = 7,76 (2H), 7,22-7,55 (8H), 6,98 (IH), 5,80 (IH), 4,93 (IH), 4,68 (IH), 3,32 (IH), 2,29 (IH), 2,00 (IH), 1,74 (IH), 1,63 (IH), 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, CDC1 3 ): δ = 7.76 (2H), 7.22-7.55 (8H), 6.98 (IH), 5.80 (IH), 4.93 (IH ), 4.68 (IH), 3.32 (IH), 2.29 (IH), 2.00 (IH), 1.74 (IH), 1.63 (IH), 1.20-1, 44 (2H), 0.81-0.98 (10H) ppm.
BEISPIEL 7aEXAMPLE 7a
(1R,2S,2'R,3 ' S,4R) -3 ' -Benzoy lamino-3 ' -phenyl-2' -triiso-propy Isily loxy-3 ' - propionsäure-l,7,7-trimethyI-bicyclo[2.2.1]hept-2-ylester(1R, 2S, 2'R, 3 'S, 4R) -3' -Benzoylamino-3 '-phenyl-2' -Triiso-propy Isily loxy-3'-propionic acid-l, 7,7-trimethylI-bicyclo [2.2.1] hept-2-yl ester
100 mg (0,65 mmol) (lR)-(+)-Borneol werden in Analogie zu Beispiel la unter Verwendung von (3R,4S)-l-benzoyl-3-triisopropyIsilyloxy-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) (IR) - (+) - borneol are reacted in analogy to Example Ia using (3R, 4S) -l-benzoyl-3-triisopropyisilyloxy-4-phenyl-2-azetidinone. After working up, 443 mg of the title compound is isolated as a crude product which is reacted further without purification.
BEISPIEL 8EXAMPLE 8
(lS^R^'R^'S^SΪO'-tert-Butoxycarbonylamino^'-hydroxy-S'-phenyl- propionsäure-l,7,7-trimethyI-bicycIo[2.2.1]hept-2-ylester(IS ^ R ^ 'R ^' S ^ SΪO'-tert-butoxycarbonylamino ^ '- hydroxy-S'-phenyl-propionic acid-l, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl ester
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.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.
Η-NMR (300MHz, CDC13): δ = 7,21-7,45 (5H), 5,44 (IH), 5,22 (IH), 5,08 (IH), 4,48 (IH), 3,16 (IH), 2,38 (IH), 1,96 (IH), 1,79 (IH), 1,73 (IH), 1,20-1,50 (11H), 1,06 (IH), 0,94 (3H), 0,89 (3H), 0,87 (3H) ppm.Η NMR (300 MHz, CDC1 3 ): δ = 7.21-7.45 (5H), 5.44 (IH), 5.22 (IH), 5.08 (IH), 4.48 (IH) , 3.16 (IH), 2.38 (IH), 1.96 (IH), 1.79 (IH), 1.73 (IH), 1.20-1.50 (11H), 1.06 (IH), 0.94 (3H), 0.89 (3H), 0.87 (3H) ppm.
BEISPIEL 8aEXAMPLE 8a
(lS,2R,2,R,3'S,4S)-3'-tert-Butoxycarbonylamino-3'-phenyl-2'-trüso- propylsilyloxy-3'-propionsäure-l,7,7-trimethyl-bicycIo[2.2.1]hept-2-yIester(IS, 2R, 2 , R, 3'S, 4S) -3'-tert-butoxycarbonylamino-3'-phenyl-2'-trisopropylsilyloxy-3'-propionic acid-l, 7,7-trimethyl-bicyclo [2.2. 1] hept-2-yester
100 mg (0,65 mmol) (lS)-(-)-Borneol werden in Analogie zu Beispiel la umgesetzt. Nach Aufarbeitung isoliert man 412 mg der Titelverbindung als Rohprodukt, das ohne Reinigung weiter umgesetzt wird.100 mg (0.65 mmol) (IS) - (-) - borneol are reacted in analogy to example la. After working up, 412 mg of the title compound is isolated as a crude product which is reacted further without purification.
BEISPIEL 9EXAMPLE 9
(lS,2R,2'R,3'S,4S)-3'-BenzoyIamino-2'-hydroxy-3'-phenyI-propionsäure-l,7,7- trimethyl-bicyclo [2.2.1] hept-2-yIester(IS, 2R, 2'R, 3'S, 4S) -3'-benzoylamino-2'-hydroxy-3'-phenyl-propionic acid-l, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yIester
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.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.
'H-NMR (300MHZ, CDC13): δ = 7,77 (2H), 7,24-7,55 (8H), 7,02 (IH), 5,73 (IH), 5,03 (IH), 4,65 (IH), 3,30 (IH), 2,38 (IH), 1,95 (IH), 1,78 (IH), 1,71 (IH), 1,18-1,43 (2H), 1,03 (IH), 0,89 (3H), 0,86 (3H), 0,79 (3H) ppm. BEISPIEL 9a'H NMR (300 MHz, CDC1 3 ): δ = 7.77 (2H), 7.24-7.55 (8H), 7.02 (IH), 5.73 (IH), 5.03 (IH ), 4.65 (IH), 3.30 (IH), 2.38 (IH), 1.95 (IH), 1.78 (IH), 1.71 (IH), 1.18-1, 43 (2H), 1.03 (IH), 0.89 (3H), 0.86 (3H), 0.79 (3H) ppm. EXAMPLE 9a
(lS,2R,2'R^'S,4S)-3'-Benzoylamino-3'-phenyl-2,-triiso-p^opylsilyIoxy-3,- propionsäure-l,7,7-trimethyl-bicyclo[2.2.1]hept-2-ylester(IS, 2R, 2'R ^ 'S, 4S) -3'-benzoylamino-3'-phenyl-2 , -triiso-p ^ opylsilyIoxy-3 , - propionic acid-l, 7,7-trimethyl-bicyclo [2.2 .1] hept-2-yl ester
100 mg (0,65 mmol) (lS)-(-)-Borneol werden in Analogie zu Beispiel la unter Verwendung von (3R,4S)-l-benzoyl-3-triisopropylsiIyloxy-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) (IS) - (-) - borneol are reacted in analogy to Example Ia using (3R, 4S) -l-benzoyl-3-triisopropylsilyloxy-4-phenyl-2-azetidinone. After working up, 401 mg of the title compound is isolated as a crude product which is reacted further without purification.
BEISPIEL 10EXAMPLE 10
(lR,2S,2'Rr3,S,4R,5R)-3'-tert-ButoxycarbonyIamino-2'-hydroxy-3'-phenyI- propionsäure-S-hydroxy-l,7,7-trimethyl-bicycIo[2.2.1]hept-2-ylester(1R, 2S, 2'R r 3 , S, 4R, 5R) -3'-tert-butoxycarbonylamino-2'-hydroxy-3'-phenyl-propionic acid-S-hydroxy-l, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl ester
43 mg (73 //mol) des nach Beispiel 10a dargestellten Silylethers werden in Analogie zu Beispiel 1 umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 17 mg (39 //mol, 54%) der Titelverbindung ais farblosen amorphen Feststoff.43 mg (73 // mol) of the silyl ether shown in Example 10a are reacted analogously to Example 1. After working up and purification, 17 mg (39 // mol, 54%) of the title compound is isolated as a colorless amorphous solid.
'H-NMR (200MHZ, CDC13): δ = 7,36 (5H), 5,21 (IH), 5,20 (IH), 4,86 (IH), 4,50 (IH), 4,00 (IH), 2,40 (IH), 1,78 (IH), 1,52 (IH), 1,38 (9H), 1,18 (3H), 0,90 (7H) ppm.'H NMR (200MHZ, CDC1 3 ): δ = 7.36 (5H), 5.21 (IH), 5.20 (IH), 4.86 (IH), 4.50 (IH), 4, 00 (IH), 2.40 (IH), 1.78 (IH), 1.52 (IH), 1.38 (9H), 1.18 (3H), 0.90 (7H) ppm.
BEISPIEL 10aEXAMPLE 10a
(lR,2S,2'R,3,S,4R,5R)-3,-tert-Butoxycarbonylamino-2'-triisopropyIsilyIoxy-3'. phenyl-propionsäure-5-hydroxy-l,7,7-trimethyI-bicycIo[2.2.1]hept-2-yIester(1R, 2S, 2'R, 3 , S, 4R, 5R) -3 , -tert-butoxycarbonylamino-2'-triisopropyisilyIoxy-3 '. phenyl-propionic acid-5-hydroxy-l, 7,7-trimethyl-bicyclo [2.2.1] hept-2-yl ester
40 mg (0,23 mmol) des nach Beispiel 10b dargestellten Diols werden in Analogie zu Beispiel la umgesetzt. Nach Aufarbeitung und Reinigung isoliert man 32 mg (0,054 mmol; 23%) der Titelverbindung als farblosen amorphen Feststoff. Η-NMR (200MHz, CDC13): δ = 7,28 (5H), 5,52 (IH), 5,10 (IH), 4,82 (IH), 4,56 (IH), 3,93 (IH), 2,38 (2H), 1,76 (IH), 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. Η NMR (200MHz, CDC1 3 ): δ = 7.28 (5H), 5.52 (IH), 5.10 (IH), 4.82 (IH), 4.56 (IH), 3.93 (IH), 2.38 (2H), 1.76 (IH), 1.60-0.80 (32H) ppm.
BEISPIEL 10bEXAMPLE 10b
(lR,2S,4R,5R)-l,7,7-Trimethyl-bicycIo[2.2.1]heptan-2,S-dioI(IR, 2S, 4R, 5R) -l, 7,7-trimethyl-bicyclo [2.2.1] heptane-2, S-dioI
170 mg (0,8 mmol) des nach Beispiel lc dargestellten Acetates werden unter170 mg (0.8 mmol) of the acetate shown in Example 1c are under
Stickstoffatmosphäre in 6 ml wasserfreiem Diethylether gelöst, mit 50 mgNitrogen atmosphere dissolved in 6 ml of anhydrous diethyl ether, with 50 mg
Lithiumaluminiumhydrid versetzt und eine Stunde bei 23°C gerührt. Anschließend werden unter Eiskühlung zuerst 5 Tropfen Methanol anschließend so lange tropfenweiseLithium aluminum hydride added and stirred at 23 ° C for one hour. Subsequently, 5 drops of methanol are then added dropwise while cooling with ice
Wasser zugegeben, bis sich ein feinkörniger Niederschlag gebildet hat. Den nachAdd water until a fine-grained precipitate has formed. The after
Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durchFiltration and removal of solvent residue obtained are purified by
Chromatographie an Kieselgel mit einem Laufmittelgemisch aus Methyl-tert.-butylether und Petrolether. Isoliert werden 93 mg (0,55 mmol, 68%) der Titelverbindung als farblose Kristalle.Chromatography on silica gel with an eluent mixture of methyl tert-butyl ether and petroleum ether. 93 mg (0.55 mmol, 68%) of the title compound are isolated as colorless crystals.
Η-NMR (200MHZ, CDCI3): δ = 3,90 (2H), 2,30 (2H), 1,72 (IH), 1,38 (IH), 1,12 (3H),Η NMR (200 MHz, CDCI 3 ): δ = 3.90 (2H), 2.30 (2H), 1.72 (IH), 1.38 (IH), 1.12 (3H),
0,91 (3H), 0,86 (3H), 0,78 (IH) ppm. 0.91 (3H), 0.86 (3H), 0.78 (IH) ppm.

Claims

PATENTANSPRÜCHE PATENT CLAIMS
1. Die Borneolderivate der allgemeinen Formel I1. The borneol derivatives of the general formula I
Figure imgf000018_0001
worin
Figure imgf000018_0001
wherein
R1 einen gegebenenfalls durch Halogenatome, Cj^-Alkylgruppen, C1-C4-R 1 is optionally substituted by halogen atoms, C j ^ alkyl groups, C1-C4
Alkoxygruppen, C^-Cg -Alkoxycarbonylgruppen oder Cj-Cg-Alkoxy groups, C ^ -Cg alkoxycarbonyl groups or C j -Cg-
Acyloxygruppen substituierter Phenylrest darstellt, R2 ein Wasserstoffatom, eine C1-C4-Alkylgruppe, substituiertes Aryl, eineCr Represents acyloxy substituted phenyl, R 2 is a hydrogen atom, a C 1 -C 4 alkyl, substituted aryl, a C r
Cö-AIkoxycarbonylgruppe oder eine Ci-Gg-Acylgruppe symbolisiert, R3 ein Wasserstoffatom, eine C1-C4-Alkylgruppe, eine CrC4-Acylgruppe oder eine Tri-C1-C4-alkylsilylgruppe bedeutet und worin R4 und R7 ein Wasserstoffatom, einen Cj-Qi-Alkylrest oder einen gegebenenfalls durchCö-alkoxycarbonyl group or a Ci-Gg acyl group, R 3 represents a hydrogen atom, a C 1 -C 4 alkyl group, a C r C 4 acyl group or a tri-C 1 -C 4 alkylsilyl group and wherein R 4 and R 7 represents a hydrogen atom, a C j -Qi-alkyl radical or one optionally through
Halogenatome, C1-C4-Alkylgruppe, Cj-Cp-Alkoxygruppen, CrC4-Halogen atoms, C 1 -C 4 alkyl group, C j -Cp alkoxy groups, C r C 4 -
Alkoxycarbonylgruppen oder Cj-Cg-Acyloxygruppen substituierterAlkoxycarbonylgruppen or Cj-Cg-Acyloxygruppen substituted
Phenylrest bedeuten und R5 und R6 ein Wasserstoffatom, eine Hydroxygruppe, oder eine Ci-Cg-Acyloxygruppe darstellen oder gemeinsam eine Kohlenstoff-Kohlenstoffbindung oder einPhenyl radical and R 5 and R 6 represent a hydrogen atom, a hydroxy group, or a Ci-Cg-acyloxy group or together represent a carbon-carbon bond or a
Sauerstoffatom symbolisieren oder R4 und R5 und /oder R6 und R7 jeweils gemeinsam eine Carbonylgruppe, eine C1-C4-Symbolize oxygen atom or R 4 and R 5 and / or R 6 and R 7 each together represent a carbonyl group, a C 1 -C 4 -
Alkylidengruppe oder gewünschtenfalls durch eine C1-C3-Alkylgruppe substituierte Oxirangruppe bedeuten, sowie gegebenenfalls deren Salze mit physiologisch verträglichen Säuren, sowie deren α- , ß- oder γ-Cyclodextrinclathrateund die in Liposomen verkapselten Verbindungen der allgemeinen Formel I bedeuten.Alkylidene group or oxirane group substituted by a C 1 -C 3 alkyl group if desired, 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.
2. Arzneimittel, bestehend aus einer oder mehrerer Verbindungen des Anspruches 1 und üblicher Hilfs-, Träger- und Zusatzstoffe.2. Medicament consisting of one or more compounds of claim 1 and customary auxiliaries, carriers and additives.
3. Verfahren zur Herstellung von Bomeolderivaten der allgemeinen Formel I gemäß Patentanspruch 1, dadurch gekennzeichnet, daß man einen Alkohol der allgemeinen Formel II
Figure imgf000019_0001
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 lila oder einer Carboxylverbindung der allgemeinen Formel Illb, V3. A process for the preparation of bomeol derivatives of the general formula I according to claim 1, characterized in that an alcohol of the general formula II
Figure imgf000019_0001
in which R 4 , R 5 , R 6 and R 7 have the abovementioned meanings and hydroxyl groups contained in R 5 or R 6 are optionally protected, with a lactam of the general formula lilac or a carboxyl compound of the general formula Illb, V
Figure imgf000019_0002
mit R1, R2 und R3 in der oben genannten Bedeutung und X' in der Bedeutung OH, O- C(O)-CH(OR3)-CH(NHR2)-R1, Halogen oder CrC10-Alkyl haben kann und in lila bzw. Illb enthaltenen Hydroxylgruppen gegebenenfalls geschützt sind, verestert, gegebenfalls vorhandene Doppelbindungen oxidiert, geschützte Hydroxylgruppen freisetzt und in ein Derivat der allgemeinen Formel I überführt.
Figure imgf000019_0002
with R 1 , R 2 and R 3 in the abovementioned meaning and X 'in the meaning OH, O- C (O) -CH (OR 3 ) -CH (NHR 2 ) -R 1 , halogen or C r C 10 -Alkyl and may be protected in the hydroxyl groups contained in purple or Illb, esterified, any double bonds present are oxidized, protected hydroxyl groups are released and converted into a derivative of the general formula I.
PCT/EP1996/001324 1995-03-08 1996-03-27 Novel borneols, processes for producing them and pharmaceutical use thereof WO1997035839A1 (en)

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US6610681B1 (en) 1999-08-16 2003-08-26 Revaax Pharmaceuticals, Llc Neurotherapeutic clavulanate composition and method
WO2006120568A2 (en) * 2005-05-13 2006-11-16 Advanced Scientific Developements Pharmaceutical composition containing an anti parasitic agent and an active ingredient selected from carveol, thymol, eugenol, borneol, carvacrol, alpha-ionone, or beta-ionone
CN104276947A (en) * 2014-09-19 2015-01-14 江西省林业科学院 Method for preparing dextrobornyl acetate from natural dextroborneol

Families Citing this family (3)

* Cited by examiner, † Cited by third party
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DE19509697A1 (en) * 1995-03-08 1996-09-12 Schering Ag New borneol ester of 3-amino-2-hydroxy-3-phenyl-propionic acid or deriv.
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
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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DE4416374A1 (en) * 1994-05-05 1995-11-09 Schering Ag New borneol derivatives, processes for their production and their pharmaceutical use
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EP0253739A1 (en) * 1986-07-17 1988-01-20 Rhone-Poulenc Sante Process for the preparation of taxol and of desacetyl-10-taxol
WO1993006079A1 (en) * 1991-09-23 1993-04-01 Florida State University PREPARATION OF SUBSTITUTED ISOSERINE ESTERS USING METAL ALKOXIDES AND β-LACTAMS
DE4416374A1 (en) * 1994-05-05 1995-11-09 Schering Ag New borneol derivatives, processes for their production and their pharmaceutical use
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US6610681B1 (en) 1999-08-16 2003-08-26 Revaax Pharmaceuticals, Llc Neurotherapeutic clavulanate composition and method
US6627625B1 (en) 1999-08-16 2003-09-30 Revaax Pharmaceuticals, Llc Treatment of behavioral disorders with β-lactam compounds
US7842683B2 (en) 1999-08-16 2010-11-30 Revaax Pharmaceuticals, Llc Neurotherapeutic compositions and method
WO2006120568A2 (en) * 2005-05-13 2006-11-16 Advanced Scientific Developements Pharmaceutical composition containing an anti parasitic agent and an active ingredient selected from carveol, thymol, eugenol, borneol, carvacrol, alpha-ionone, or beta-ionone
WO2006120568A3 (en) * 2005-05-13 2007-08-23 Advanced Scient Developements Pharmaceutical composition containing an anti parasitic agent and an active ingredient selected from carveol, thymol, eugenol, borneol, carvacrol, alpha-ionone, or beta-ionone
CN104276947A (en) * 2014-09-19 2015-01-14 江西省林业科学院 Method for preparing dextrobornyl acetate from natural dextroborneol

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