WO1997035839A1 - Nouveaux borneols, leur procede de fabrication et leur utilisation pharmaceutique - Google Patents

Nouveaux borneols, leur procede de fabrication et leur utilisation pharmaceutique 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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WIPO (PCT)
Prior art keywords
group
alkyl
general formula
mmol
groups
Prior art date
Application number
PCT/EP1996/001324
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German (de)
English (en)
Inventor
Ulrich Klar
Hermann Graf
Siegfried Blechert
Anke Sachse
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE19509697A priority Critical patent/DE19509697A1/de
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to PCT/EP1996/001324 priority patent/WO1997035839A1/fr
Publication of WO1997035839A1 publication Critical patent/WO1997035839A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

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

L'invention concerne des dérivés du bornéol de formule générale (I), où R1 représente un reste phényle éventuellement substitué par des atomes d'halogène, des groupes alkyle C¿1?-C4, des groupes alcoxy C1-C4, des groupes alcoxycarbonyle C1-C6 ou des groupes acyloxy C1-C8; R?2¿ symbolise un atome d'hydrogène, un groupe alkyle C¿1?-C4, un aryle substitué, un groupe alcoxycarbonyle C1-C6 ou un groupe acyle C1-C8; R?3¿ signifie un atome d'hydrogène, un groupe alkyle C¿1?-C4, un groupe acyle C1-C4 ou un groupe tri-alkylsilyle C1-C4; et où R?4 et R7¿ signifient un atome d'hydrogène, un reste alkyle C¿1?-C4 ou un reste phényle éventuellement substitué par des atomes d'halogène, un groupe alkyle C1-C4, des groupes alcoxy C1-C9, des groupes alcoxycarbonyle C1-C4 ou des groupes acyloxy C1-C8, et R?5 et R6¿ représentent un atome d'hydrogène, un groupe hydroxy ou un groupe acyloxy C¿1?-C8, ou ensemble symbolisent une liaison carbone-carbone ou un atome d'oxygène, ou R?4 et R5¿ et/ou R6 et R7 signifient ensemble un groupe carbonyle, un groupe alkylidène C¿1?-C4 ou le cas échéant un groupe oxyrane substitué par un groupe alkyle C1-C3. L'invention concerne également leurs sels avec des acides physiologiquement acceptables, ainsi que leurs α, β ou η cyclodextrine-clathrates et les composés de formule générale (I) encapsulés dans des liposomes.
PCT/EP1996/001324 1995-03-08 1996-03-27 Nouveaux borneols, leur procede de fabrication et leur utilisation pharmaceutique WO1997035839A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE19509697A DE19509697A1 (de) 1995-03-08 1995-03-08 Neue Borneole, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
PCT/EP1996/001324 WO1997035839A1 (fr) 1995-03-08 1996-03-27 Nouveaux borneols, leur procede de fabrication et leur utilisation pharmaceutique

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19509697A DE19509697A1 (de) 1995-03-08 1995-03-08 Neue Borneole, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
PCT/EP1996/001324 WO1997035839A1 (fr) 1995-03-08 1996-03-27 Nouveaux borneols, leur procede de fabrication et leur utilisation pharmaceutique

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Publication Number Publication Date
WO1997035839A1 true WO1997035839A1 (fr) 1997-10-02

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WO (1) WO1997035839A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6610681B1 (en) 1999-08-16 2003-08-26 Revaax Pharmaceuticals, Llc Neurotherapeutic clavulanate composition and method
WO2006120568A2 (fr) * 2005-05-13 2006-11-16 Advanced Scientific Developements Composition pharmaceutique comprenant un agent antiparasitaire , et un actif choisi parmi le carveol , le thymol , l ugenol , le borneol , le carvacrol , l lpha- ionone ou le beta-ionone
CN104276947A (zh) * 2014-09-19 2015-01-14 江西省林业科学院 一种天然右旋龙脑制备右旋乙酸龙脑酯的方法

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19509697A1 (de) * 1995-03-08 1996-09-12 Schering Ag Neue Borneole, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
CN108558621B (zh) * 2018-05-17 2021-01-19 华南理工大学 一种柠檬醛二冰片基缩醛衍生物及其制备方法与用途
CN113845424B (zh) * 2021-10-14 2023-09-12 南京医科大学 右崁醇酯类化合物及其药物用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253739A1 (fr) * 1986-07-17 1988-01-20 Rhone-Poulenc Sante Procédé de préparation du taxol et du désacétyl-10 taxol
WO1993006079A1 (fr) * 1991-09-23 1993-04-01 Florida State University PREPARATION D'ESTERS D'ISOSERINE SUBSTITUES PAR L'UTILISATION D'ALCOXYDES METALLIQUES ET DE β-LACTAMES
DE4416374A1 (de) * 1994-05-05 1995-11-09 Schering Ag Neue Borneolderivate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
DE19509697A1 (de) * 1995-03-08 1996-09-12 Schering Ag Neue Borneole, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0253739A1 (fr) * 1986-07-17 1988-01-20 Rhone-Poulenc Sante Procédé de préparation du taxol et du désacétyl-10 taxol
WO1993006079A1 (fr) * 1991-09-23 1993-04-01 Florida State University PREPARATION D'ESTERS D'ISOSERINE SUBSTITUES PAR L'UTILISATION D'ALCOXYDES METALLIQUES ET DE β-LACTAMES
DE4416374A1 (de) * 1994-05-05 1995-11-09 Schering Ag Neue Borneolderivate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
DE19509697A1 (de) * 1995-03-08 1996-09-12 Schering Ag Neue Borneole, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (fr) * 2005-05-13 2006-11-16 Advanced Scientific Developements Composition pharmaceutique comprenant un agent antiparasitaire , et un actif choisi parmi le carveol , le thymol , l ugenol , le borneol , le carvacrol , l lpha- ionone ou le beta-ionone
WO2006120568A3 (fr) * 2005-05-13 2007-08-23 Advanced Scient Developements Composition pharmaceutique comprenant un agent antiparasitaire , et un actif choisi parmi le carveol , le thymol , l ugenol , le borneol , le carvacrol , l lpha- ionone ou le beta-ionone
CN104276947A (zh) * 2014-09-19 2015-01-14 江西省林业科学院 一种天然右旋龙脑制备右旋乙酸龙脑酯的方法

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