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EP0929570A1 - Modifizierte cytostatika - Google Patents

Modifizierte cytostatika

Info

Publication number
EP0929570A1
EP0929570A1 EP97910326A EP97910326A EP0929570A1 EP 0929570 A1 EP0929570 A1 EP 0929570A1 EP 97910326 A EP97910326 A EP 97910326A EP 97910326 A EP97910326 A EP 97910326A EP 0929570 A1 EP0929570 A1 EP 0929570A1
Authority
EP
European Patent Office
Prior art keywords
camptothecin
compounds
lysyl
tlc
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97910326A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hans-Georg Lerchen
Karsten Von Dem Bruch
Jörg Baumgarten
Michael Sperzel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
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
Application filed by Bayer AG filed Critical Bayer AG
Publication of EP0929570A1 publication Critical patent/EP0929570A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to conjugates of cytostatics and N-thiocarbonyl-modified amino acids or peptides, processes for their preparation and their use as medicaments, in particular in connection with cancer.
  • Chemotherapy for tumor diseases is accompanied by mostly serious side effects due to the toxicity of chemotherapeutic agents on proliferating cells of other tissues. Have been busy for many years
  • prodrugs which are more or less selective in the target tissue, for example by changing the pH (for example Tietze et al., DE 4 229 903), by enzymes (for example glucuronidases; Jacquesy et al., EP 511 917; Bosslet et al., EP 595 133) or by
  • Antibody-enzyme conjugates (Bagshawe et al., WO 88/07378; Senter et al., US Pat. No. 4,975,278; Bosslet et al., EP 595 133) are released. Problems with these approaches include the lack of stability of the conjugates in other tissues and organs and in particular the ubiquitous distribution of active substances, which follows the extracellular release of active substances in the tumor tissue.
  • the heterocyclic amine batracylin (1) shows a good antitumor effect in various colon cancer models (US Pat. No. 4,757,072).
  • Peptide conjugates of (1) with good in vitro activity and more favorable solubility properties are less tolerable in animal experiments than batracylin itself.
  • camptothecin derivatives About 20 years later it was found that the biological activity is due to an enzyme inhibition of topoisomerase I. Since then, the research activities have been intensified again in order to find more contractual and in vivo effective camptothecin derivatives
  • conjugates obtained in this way are easily accessible synthetically and show in vitro a similarly high activity towards different tumor cell lines and tumor xenografts as the underlying toxophore
  • the conjugates according to the invention show significantly improved solubility properties compared to the underlying cytostatics
  • the invention relates to compounds of the general formula (I)
  • Ar- ⁇ -NH-C is where n is a number 1 to n 'and n' is the maximum
  • Ar stands for an aryl radical with up to 10 carbon atoms, which, in addition to X, can optionally be mono- or polysubstituted by alkyl with up to 6 carbon atoms, alkoxy with up to 6 carbon atoms, alkoxycarbonyl with up to 6 carbon atoms, hydroxy, carboxy, carboxyalkyl with up to 6 carbon atoms, cyano, nitro, isocyanato,
  • X represents a direct single bond or alkylene with up to 6 carbon atoms
  • M stands for a mono-, di-, tri- or tetrapeptide which has the same or different groups via the ⁇ -amino group and / or via amino and / or hydroxy groups of the side chains
  • Ar-X-NH-C is linked, with further functional groups of
  • Peptide can optionally carry protective groups
  • C represents a residue of a cytostatic or a cytostatic derivative which is linked to M via an amino function or via an oxygen atom,
  • C can be an intercalating substance, a topoisomerase inhibitor, an anti-metabolite, an alkylant, a tubulin inhibitor, a tyrosine phosphokinase inhibitor, a protein kinase C inhibitor or an active substance with a different or unknown cytostati or see cytotoxic mechanism of action.
  • C can be, for example, a nucleoside, an endiin antibiotic, a quinolone or naphthyridone carbon acid or a cytotoxic peptide antibiotic e.g. be from the class of Dolastatine.
  • C can batracylin, quinolone-a, 5-fluorouracil, cytosine arabinoside, methotrexate, etoposide, camptothecin, a camptothecin derivative, daunomycin, doxorubicin,
  • Taxol Taxol, vinblastine, vincristine, dynemicin, calicheamycin, esperamycin, quercetin, suramin, erbstatin, cyclophosphamide, mitomycin C, melphalan, cisplatin, bleomycin, staurosporine or another anti neoplastic active ingredient.
  • alkyl groups is intended to include straight-chain, branched, cyclic and cycloalkyl radicals containing alkyl radicals. This definition should also apply analogously to all other radicals containing alkyl groups, such as alkoxy etc.
  • Preferred compounds of the formula (I) are those in which
  • Ar stands for a phenyl radical which is para to X, also hydroxyl, carboxy,
  • M stands for a mono-, di- or T ⁇ peptide which has the same or different groups S via the ⁇ -amino group and / or via amino and / or hydroxy groups of the side chains
  • Ar-X-N ⁇ -C is linked, with further functional groups of
  • Peptide can optionally carry protective groups
  • the peptides M preferably consist of amino acid residues which are derived from alanine, aspartic acid, glutamic acid, glycine, leucine, histidine, lysine, arginine,
  • M carries further functional groups, these are preferably unblocked
  • C for a batracyhn, methotrexate, quinolone a, etoposide, melphalan, taxol, camptothecin radical, a camptothecin modified in the A ring or B ring De ⁇ vat, a Dauomycin- or Doxorubicin residue stands, whereby C is linked to M via an amino or hydroxy function.
  • the compounds according to the invention can exist in stereoisomeric forms, for example as enantiomers or diastereomers, or as mixtures thereof, for example as a racemate.
  • the invention relates both to the pure stereoisomers and to their mixtures If necessary, the stereoisomer mixtures can be separated into the stereoisomerically uniform constituents in a known manner, for example by chromatography or by crystallization processes
  • amino acid residues can each be in the D-form or in the L-form
  • the compounds according to the invention can occur in rotation isomeric forms or as mixtures thereof as a result of a rotation inhibition
  • rotational isomer mixtures can be separated into the uniform constituents by known methods, for example by chromatography (for example HPLC) or by crystallization processes. This is possible not only at the final stage of the conjugates but also, if appropriate, at intermediate stages. If appropriate, the rotamer-pure end stages can be prepared from the rotamer-pure intermediates by suitable synthesis
  • the compounds according to the invention can also be present in the form of their salts.
  • salts with organic or inorganic bases or acids and internal salts may be mentioned here.
  • the acids which can be added preferably include hydrohalic acids, such as, for example, hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as, for example, acetic acid, trifluoroacetic acid, Maleic acid, malonic acid, oxalic acid,
  • hydrohalic acids such as, for example, hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, furthermore phosphoric acid, nitric acid, sulfuric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as, for example, acetic acid, trifluoroacetic acid, Maleic acid, malonic acid, oxalic acid,
  • Gluconic acid succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid as well as sulfonic acids, such as p-toluenesulfonic acid, 1,5-naphthane disulfonic acid or camphorsulfonic acid
  • Physiologically acceptable salts can also be metal or ammonium salts of such compounds according to the invention which have a free carboxyl group
  • Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts which are derived from ammonia or organic amines such as, for example, ethylamine, di- or t ⁇ ethylamine, di- or t ⁇ ethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, Ethylenediamine or phenethylamine
  • the invention further relates to a process for the preparation of compounds of the general formula (I), characterized in that compounds of the general formula (II)
  • the conjugates according to the invention can be prepared, for example, by linking cytostatics derivatives carrying hydroxyl or amino groups (e.g. batracylin, quinolones or camptothecins) to activated carboxyl components, which in turn can be parts of protected amino acids, peptides or N-thiocarbonyl-modified peptides.
  • cytostatics derivatives carrying hydroxyl or amino groups e.g. batracylin, quinolones or camptothecins
  • carboxyl components which in turn can be parts of protected amino acids, peptides or N-thiocarbonyl-modified peptides.
  • the compounds of the general formula (II) can be obtained by linking protected amino acid building blocks to amino or hydroxy functions of C using customary methods of peptide chemistry and, if appropriate, building up a peptide chain by gradually introducing further amino acid building blocks.
  • peptide building blocks carrying protective groups can also be linked to C using customary methods.
  • the reactions can be carried out at various pressure and temperature ratios, for example from 0.5 to 2 bar or from -30 to + 100 ° C., in suitable solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, chloroform, and lower alcohols , Acetonitrile, dioxane, water or in mixtures of the solvents mentioned.
  • suitable solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, chloroform, and lower alcohols , Acetonitrile, dioxane, water or in mixtures of the solvents mentioned.
  • adducts with carbodiimides for example N, N'-diethyl, N, N'-diisopropyl, N, N'-dicyclo- hexylcarbodiimide, N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride, N-cyclohexyl-N '- (2-morpholinoethyl) -carbodiimide-metho-p-toluenesulfonate, or carbonyl compounds such as carbonyldiimidazole, or 1, 2- Oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-
  • carbodiimides for example N, N'-diethyl
  • 1,2-dihydroquinoline or propanephosphonic anhydride, or isobutylchloroform, or benzotriazoilyloxy-tris (dimethylamino) phosphonium hexafluorophosphate, 1-hydroxybenzotriazole or hydroxysuccinimide ester.
  • Triethylamine, Hünig base, ethyldiisopropylamine, pyridine, N, N-dimethylaminopyridine or others can be used as bases, for example.
  • the protective groups known in peptide chemistry for example of the urethane, alkyl, acyl, ester or amide type, can be used as protective groups for any further reactive functions in the cytostatic part or for third functions of the amino acids.
  • Amino protecting groups in the context of the invention are the usual amino protecting groups used in peptide chemistry.
  • benzyloxycarbonyl (Cbz) 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5 -dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, (Boc) allyloxycarbonyl, vinyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert -butoxycarbonyl, menthyloxycarbonyl, 4-nitrophenoxycarbonyl, fluoro-enyl-9-methoxycarbonyl (Fmoc), formyl, acet
  • Particularly preferred protecting groups are Fmoc, Boc and Cbz.
  • Protective groups can be split off in the corresponding reaction steps, for example by exposure to acid or base, hydrogenolytically or in some other way reductively.
  • Biological testing can be split off in the corresponding reaction steps, for example by exposure to acid or base, hydrogenolytically or in some other way reductively.
  • the human colon tumor cell lines SW 480 and HT 29 (ATCC No. CCL 228 and HBT-38) and the mouse melanoma cell line B16F10 were grown in Roux dishes in RPMI 1640 medium with the addition of 10% FCS. It was then trypsinized and taken up in RPMI plus 10% FCS to a cell number of 50,000 cells / ml. 100 ⁇ l of cell suspension / well were placed in a 96 microwell plate and incubated for 1 day at 37 ° C. in a C0 9 incubator. A further 100 ⁇ l of RPMI medium and 1 ⁇ l of DMSO with the test substances were then added.
  • Microwell 40 ⁇ l MTT solution (3- (4,5-dimethyIthiazol-2-yl) -2,5-diphenyltetrazoline bromide) with an initial concentration of 5 mg / ml H., 0 was added. It was
  • the cytotoxic effect is given in Table 1 as an IC 50 value for the SW 480 and HT 29 and B16F10 cell lines:
  • Bone marrow cells were rinsed from the mouse femur. 10 5 cells are in McCoy 5A medium (0.3% agar) together with recombinant murine GM
  • CSF Genzyme; stem cell colony formation
  • substances (10 "4 to 100 ⁇ g / ml) were incubated at 37 ° C. and 7% CO 2. 7 days later the colonies ( ⁇ 50 cells) and clusters (17-50 cells ) counted.
  • Athymic nude mice (NMRI nu / nu strain) were used for all in vivo experiments to investigate the inhibition of tumor growth.
  • the selected large cell lung carcinoma LXFL 529 was by serial passage in Nude mice developed.
  • the human origin of the tumor was proven by iso-enzymatic and immunohistochemical methods.
  • the tumor was implanted subcutaneously in both flanks of 6 to 8 week old nu / nu nude mice. Depending on the doubling time, the treatment was started as soon as the tumors had reached a diameter of 5-7 mm. The mice were randomized to the treatment group and the control group (5 mice per group with 8-10 evaluable tumors). The individual tumors in the control group all grew progressively.
  • the size of the tumors was measured in two dimensions using a slide gauge.
  • the tumor volume which correlates well with the cell number, was then used for all evaluations.
  • the volume was calculated according to the formula "length x width x width / 2" ([axb 2 ] / 2, a and b stand for two diameters arranged at right angles).
  • Relative tumor volume (RTV) values were calculated for each tumor by dividing the tumor size on day X by the tumor size on day 0 (at the time of randomization). The mean values of the RTV were then used for the further evaluation.
  • the final measured value was the inhibition of the increase in tumor volume (tumor volume of the test group / control group, T / C, in percent).
  • the compounds were applied intraperitoneally (i.p.) on days 1, 2 and 3 after randomization.
  • Results The compound from Example 4.4) shows the therapeutic activity of the conjugates according to the invention against the large-cell human lung tumor xenograph LXFL 529. Therapy leads to tumor remission at the maximum tolerable dose (MTD) and half of the MTD.
  • MTD maximum tolerable dose
  • the compounds according to the invention have a surprisingly strong cytotoxic activity against various, both in vitro and in vivo
  • Tumors especially those of the lungs and colon, are associated with a high selectivity towards non-malignant cells.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for the preparation of these preparations.
  • the active ingredient (s) can optionally also be in microencapsulated form in one or more of the above-mentioned carriers.
  • the therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further active pharmaceutical ingredients.
  • the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg / kg of body weight per 24 hours, optionally in the form multiple doses to achieve the desired results.
  • a single dose contains the active ingredient (s) according to the invention preferably in amounts of about 1 to about 80, in particular 3 to 30 mg / kg of body weight.
  • Remaining protective groups are then removed in a second step by methods known from the literature (a fluorenyl-9-methoxycarbonyl group e.g. with piperidine in absolute dimethylformamide at room temperature; a tert-butoxycarbonyl group e.g. with trifluoroacetic acid in absolute dichloromethane at room temperature).
  • N-Benzyloxycarbonyl-D-alanine (3.9 g, 17.5 mmol) is reacted with batracylin (4.1 g, 16.4 mmol) analogously to Example I 1 a.
  • batracylin 4.1 g, 16.4 mmol
  • the mixture is treated with ethyl acetate made up to 300 ml and immediately heated to boiling for 10 min.
  • the mixture is then allowed to cool to room temperature, filtered and the filter material is boiled again with ethyl acetate (200 ml) by cooling to 0 ° C. with stirring and filtration gives yellow crystals.
  • N- (tert-Butoxycarbonyl) -D-alanine (3.6 g, 19.2 mmol) and 2-isobutoxy-1-isobutoxycarbonyl-1, 2-dihydroquinoline (5.8 g, 19.2 mmol ) are dissolved in 200 ml of dimethylformamide.
  • quinolone-a (4 g, 9.6 mmol) and ethyldiisopropylamine (3.3 ml) are added and the mixture is treated with ultrasound for 10 h.
  • the mixture is concentrated, the residue is taken up in dichloromethane and precipitated with ether. After filtration, washing with ether and drying in a high vacuum, 4.58 g (81%) of the target product are obtained, which is reacted without further purification.
  • N ⁇ - (tert-Butoxycarbonyl) -N ⁇ - (fluorenyl-9-methoxycarbonyl) -lysine (1.57 g, 3.36 mmol) is dissolved in dimethylformamide (25 ml) and at 0 ° C with N-
  • Camptothecin 500 mg, 1.44 mmol are dissolved in absolute dimethylformamide (20 ml) and then with 4-dimethylaminopyridine (50 mg) and N-tert-butoxycarbonylalanine-N-carboxy-anhydride (775 mg, 3, 6 mmol) was added. After 3 h, a further 775 mg (3.6 mmol) of N-tert-butoxycarbonyl-alanine-N-carboxy-anhydride are added and the suspension is treated with ultrasound for 16 h. The mixture is concentrated, the raw material is taken up in dichloromethane (50 ml) and 5 ml of trifluoroacetic acid are added at 0 ° C. After 30 min.
  • Example I.4.a The conjugate from Example I.4.a is linked according to standard instructions (see Example I. la) with N ⁇ - (tert-butoxycarbonyl) -N ⁇ - (fluorenyl-9-methoxycarbonyl) lysine and then in analogy to Example Il unblocked at the ⁇ -amino function.
  • the target compound is obtained in a yield of 24% [TLC (acetonitrile / water 20: 1): R f - 0.15].
  • This camptothecin derivative is produced according to Wall et al (J Med Chem 29 (1986), 2358) from the S-configured, enantiomerically pure tricyclic compound, which can be obtained, for example, by racemate resolution
  • Dimethylformamide is stirred with 9.64 g (30.0 mmol) of O-benzyl-N- (tert-butoxycarbonyl) -serine-N-carboxylic acid anhydride and 367 mg (3.0 mmol) of 4- (N, N-dimethylamino) -pyridine added. After stirring for 8 h at 60 ° C., a further 4.82 g (15.0 mmol) of O-benzyl-N- (tert-butoxycarbonyl) -serine-N-carboxylic acid anhydride and 183.5 mg (1.5 mmol) 4 are added - (N, N-Dimethylamino) pyridine and stir for three
  • the compound is prepared using the method described in I 5 a from 392.4 mg (1.0 mmol) of 20 (S) -7-ethyl-10-hydroxy-camptothecin (S Sawada et al, Chem Pharm Bull 39 (1991) 3183-3188) and a total of 2.43 g (10.0 mmol) of N- (tert-butoxycarbonyl) -valine-N-carboxylic acid anhydride within 6 days.
  • Hydrochloride The compound is dissolved in dioxane / water and converted into the hydrochloride with one equivalent of 0.1 N hydrochloric acid. The resulting solution is then lyophilized.
  • Trifluoroacetate salt-free precursor 68% over 2 stages [TLC (acetonitrile / water / glacial acetic acid
  • Trifluoroacetate salt-free precursor 79% over 2 stages [TLC (acetonitrile / water / glacial acetic acid
  • Trifluoroacetate salt-free precursor 86% over 2 stages [TLC (acetonitrile / water / glacial acetic acid
  • Trifluoroacetate salt-free precursor 67% over 2 stages [TLC (acetonitrile / water / glacial acetic acid
  • Trifluoroacetate salt-free precursor 55% over 2 stages [TLC (acetonitrile / water / glacial acetic acid
  • Hydrochloride The compound is dissolved with dioxane / water and converted into the hydrochloride with one equivalent of 0.1N hydrochloric acid. The resulting solution is then lyophilized.
  • Trifluoroacetate salt-free precursor 71% over 2 stages [TLC (acetonitrile / water / glacial acetic acid
  • Sodium salt The compound is suspended in water and one equivalent of a 0.1 N sodium hydroxide solution is added. The resulting solution is then lyophilized.
  • Hydrochloride water is added to the compound and the suspension is acidified to pH 2 with 1N hydrochloric acid. The resulting solution is filtered through Celite and then lyophilized. 98/15571
  • Hydrochloride The compound is dissolved in dioxane / water and converted into the hydrochloride with one equivalent of 0.1 N hydrochloric acid. The resulting solution is then lyophilized.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP97910326A 1996-10-04 1997-09-22 Modifizierte cytostatika Withdrawn EP0929570A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19640970 1996-10-04
DE19640970A DE19640970A1 (de) 1996-10-04 1996-10-04 Modifizierte Cytostatika
PCT/EP1997/005189 WO1998015571A1 (de) 1996-10-04 1997-09-22 Modifizierte cytostatika

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US (1) US20020173468A1 (ja)
EP (1) EP0929570A1 (ja)
JP (1) JP2001502308A (ja)
AU (1) AU4776697A (ja)
DE (1) DE19640970A1 (ja)
WO (1) WO1998015571A1 (ja)

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EP1355675A1 (en) * 2001-01-30 2003-10-29 Universite Catholique De Louvain Anti-tumor compounds
US20060014697A1 (en) 2001-08-22 2006-01-19 Travis Mickle Pharmaceutical compositions for prevention of overdose or abuse
US7169752B2 (en) 2003-09-30 2007-01-30 New River Pharmaceuticals Inc. Compounds and compositions for prevention of overdose of oxycodone
US7700561B2 (en) * 2002-02-22 2010-04-20 Shire Llc Abuse-resistant amphetamine prodrugs
US7105486B2 (en) * 2002-02-22 2006-09-12 New River Pharmaceuticals Inc. Abuse-resistant amphetamine compounds
US7659253B2 (en) 2002-02-22 2010-02-09 Shire Llc Abuse-resistant amphetamine prodrugs
JP4898445B2 (ja) * 2003-05-29 2012-03-14 シャイア エルエルシー 乱用抵抗性アンフェタミン化合物類
CN108822120A (zh) * 2018-07-11 2018-11-16 浙江工业大学 Fl118氨基酸盐酸盐及其制备方法与应用
CN111171041B (zh) * 2018-11-12 2021-07-27 中国海洋大学 20位取代的喜树碱衍生物及其制备方法和应用

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WO1998015571A1 (de) 1998-04-16
AU4776697A (en) 1998-05-05
US20020173468A1 (en) 2002-11-21
JP2001502308A (ja) 2001-02-20
DE19640970A1 (de) 1998-04-16

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