EP0696285A1 - Wasserloesliche camptothecinderivate und ihre verwendung als antitumormittel - Google Patents

Wasserloesliche camptothecinderivate und ihre verwendung als antitumormittel

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Publication number
EP0696285A1
EP0696285A1 EP94915931A EP94915931A EP0696285A1 EP 0696285 A1 EP0696285 A1 EP 0696285A1 EP 94915931 A EP94915931 A EP 94915931A EP 94915931 A EP94915931 A EP 94915931A EP 0696285 A1 EP0696285 A1 EP 0696285A1
Authority
EP
European Patent Office
Prior art keywords
camptothecin
lower alkyl
compound
ethylenedioxy
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94915931A
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English (en)
French (fr)
Inventor
Jeffrey Mark Besterman
Michael Glenn Evans
Michael Joseph Luzzio
Peter Leslie Myers
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.)
SmithKline Beecham Corp
Original Assignee
Glaxo Wellcome Inc
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Filing date
Publication date
Application filed by Glaxo Wellcome Inc filed Critical Glaxo Wellcome Inc
Publication of EP0696285A1 publication Critical patent/EP0696285A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Definitions

  • the present invention relates to water soluble, camptothecin derivatives substituted in the 7 position, their use in the treatment of tumors and methods of their preparation.
  • Camptothecin a natural, cytotoxic alkaloid, is a topoisomerase I inhibitor and potent antitumor agent. It was first isolated from the leaves and bark of the Chinese plant, Camptotheca accuminata, by Wall, et. al. (J. Am. Chem. Soc, 88 3888 (1966)).
  • camptothecin is a fused ring system, composed of a quinoline (A and B), fused to a pyrrolidine ring (C), fused to an alpha-pyridone ring (D) which in turn is fused to a lactone ring (E).
  • Cytotoxic agents are often employed to control or eradicate tumors i.e., they are chemotherapeutic agents. Camptothecin's cytotoxic activity is thought to be di ⁇ rectly related to camptothecin's potency as a topoisomerase inhibitor. [For detailed explanations of the topoisomerase function see A. Lehninger, Principles of Biochemistry, 813, Worth Publishers, New York (1982); L. F.
  • camptothecin has been shown to be effective in the treatment of leukemia (L-1210) and certain solid tumors in laboratory animals, e.g., see Chem. Rev. 23, 385 (1973) and Cancer Treat. Rep., 60, 1007 (1967).
  • Camptothecin is essentially insoluble in physiologically compatible, aqueous media, and must be modified to make it suffi ⁇ ciently soluble for parenteral administration, a preferred mode for antitumor treat ⁇ ment. It can be made soluble by forming its sodium salt, that is, by opening the lactone with sodium hydroxide (see F.M. Muggia, et al., Cancer Chemotherapy Reports, pt. 1 , 56, No.4, 515 (1972)). However, M. C. Wani, et al., J. Med. Chem., 23, 554 (1980), reported that the alpha-hydroxy lactone moiety of ring E is an abso ⁇ lute requirement for antitumor activity.
  • Miyasaka, et al. U.S. Patent No. 4,399,282 discloses a group of camptothecin derivatives substituted at the 7 position with, inter alia, hydroxymethyl and alkoxymethyl. Further, Miyasaka, et. al. in U.S. patent No. 4,399,276 discloses camptothecin-7-aldehyde and certain related aldehyde derivatives such as acetals, oximes and hyrazones. More recently, Vishnuvajjala, et al., in U.S. Patent No.
  • One aspect pf the present invention is the water-soluble camptothecin analogs of formula (I),
  • R 1 represents: hydrogen, lower alkyl, (C3.7)cycloalkyl, (C3.7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, amino lower alkyl, lower alkoxy lower alkyl or (CH2)tAr wherein: t is 0 to 5 and
  • Ar represents phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl; or phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl, with one or more substituents independently selected from hydroxy, methoxy, halogen, and amino; and R 2 represents: diphenylmethyl or(CH2)tAr; or
  • R 1 and R 2 taken together with the linking nitrogen represent; N-tetrahydroquinolyl or N-tetrahydroisoquinolyl;
  • Pharmaceutically acceptable salts include, but are not limited to salts with in ⁇ organic acids such hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or salts with an organic acid such as acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, palmoate, salicylate and stearate.
  • Other acids such as oxalic, while not in themselves phar ⁇ maceutically acceptable, may be useful as intermediates in obtaining the com- pounds of the invention and their pharmaceutically acceptable salts.
  • Another aspect of the invention is a method of inhibiting topoisomerase Type I in mammalian cells comprising administering to a patient a topoisomerase inhibit ⁇ ing amount of a compound of formula (I), and a method of treating a tumor in a mammal comprising administering to a mammal bearing a tumor, an effective anti ⁇ tumor amount of a compound of formula (I).
  • a further aspect comprises pharma ⁇ ceutical formulations containing a compound of formula (I) as an active ingredient.
  • the term “lower” in reference to alkyl and alkoxy means 1-6 carbons, especially 1-3 carbons, and in reference to alkenyl means 3-6 carbons (provided that the double bond is not attached to the carbon which is attached to the nitrogen).
  • aryl means aromatic ring substituents, e.g., phenyl, napthyl, furyl, pyridyl, N-methylpyrrolyl or imidazolyl.
  • the group “(CH2)t” also includes branched alkylene chains where branching is possible.
  • N-tetrahydroquinolyl and “N-tetrahydroisoquinolyl” are defined as follows:
  • the lactone ring, i.e., ring E, of the camptothecin moiety may be opened by alkali metal or alkaline-earth metal bases, for example sodium hydroxide or calcium hydroxide, to form alkali metal or alkaline-earth metal salts of the corresponding open E ring form of the compounds of formula (I).
  • alkali metal or alkaline-earth metal bases for example sodium hydroxide or calcium hydroxide
  • the open E ring form may advantageously be purified by conventional recrystallization techniques. Accordingly, said open E ring form may then be used as an intermediate to form the compounds of formula (I), for example by treatment with acid, e.g., hydrochloric acid, and thereby produce a purified form of the compounds of formula (I).
  • the camptothecin moiety has an asymmetric carbon atom at the 20 position making two enantiomeric forms, i.e., "R” and “S” configurations, possible.
  • This invention includes both enantiomeric forms and any combinations of these forms.
  • the nomen ⁇ clature convention, "(R,S)”, denotes a racemic (approximately equal portion) mix- ture of the R and S enantiomers while "(R)” and “(S)” denote essential optically pure R and S enantiomers respectively.
  • other forms of the compound of formula (I) such as solvates, hydrates, polymorphs and the like.
  • R 1 represents: hydrogen, lower alkyl, (C3_7)cycloalkyl, (C3 relieve7)cycloalkyl lower alkyl, lower alkenyl, hydroxy lower alkyl, amino lower alkyl, lower alkoxy lower alkyl or (CH2)tAr wherein: t is 0 to 5 and
  • Ar represents phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl; or phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl, with one or more substituents selected from hydroxy, methoxy, halogen, and amino; or R 2 represents: diphenylmethyl or(CH2)tAr; and
  • R 1 and R 2 taken together with the linking nitrogen represent; N-tetrahydroquinolyl or N-tetrahydroisoquinolyl;
  • Another sub group of compounds of the present invention are the compounds of formula (I) wherein: n represents the integer 1 or 2; and i) R 1 represents: hydrogen, (C1-3) alkyl or amino (C1-3) alkyl; and
  • R2 represents: diphenylmethyl or(CH 2 )tAr; wherein: t is 1 to 3 and
  • Ar represents phenyl, 2-furyl, 2-pyridyl, 4-pyridyl 2-N- methylpyrrolyl, 4-imidazolyl; or phenyl, 2-furyl, 2-pyridyl, 4- pyridyl, 2-N-methylpyrrolyl, 4-imidazolyl, with one to two substituents selected from hydroxy, methoxy, halogen, and amino; or
  • R 1 and R 2 taken together with the linking nitrogen represent N-tetrahydroisoquinolyl
  • Ar represents phenyl, furyl, pyridyl, N-methylpyrrolyl, imidazolyl or phenyl substituted with one or two substituents independently selected from hydroxy, methoxy, halogen and amino.
  • Typical Ar groups include phenyl and substituted phenyl, 2-furyl, 2-pyridyl, 4- pyridyl, 2-N-methylpyrrolyl and 4-imidazolyl.
  • Ar is substituted phenyl or 4-pyridyl.
  • R 1 represents hydrogen, lower alkyl, lower alkylaminolower alkyl or -(CH2)tAr, especially hydrogen or lower alkyl.
  • t is 1, 2, or 3, especially 1 and n is 1 or 2, especially 2.
  • a compound of formula (II), wherein X is a leaving group (as defined in J. March, Advanced Organic Chemistry, 3rd. Ed., page 179, John Wiley & Sons, New York (1985)), for example, a halogen, e.g., chloro, may be reacted with a compound of formula (III) according to the method taught in US Patent 4,894,456 (hereinafter, '456), issued January 16, 1990 to Wall et al., incor ⁇ porated herein by reference, to yield a compound of formula (IV).
  • the reaction of Step 1 is preferably carried out in the presence of an acid or base catalyst.
  • the acid catalyst is preferably a strong mineral acid, for example hydrochloric, nitric, sulfuric and phosphoric or a strong organic acid such as C-t- ⁇ alkanoic acids and C ⁇ -i2 arylsulfonic acids, especially p-toluenesulfonic acid.
  • the base catalyst is preferably an inorganic base, for example sodium and potassium carbonate and sodium and potassium bicarbonate or an organic base such as a sterically hindered base, for example, triethylamine and diisopropylamine.
  • This reaction may be carried out neat or in the presence of a polar or non- polar solvent.
  • Preferred polar solvents are C1-6 alcohols, C1-6 ethers, and dimethylformamide.
  • Preferred non-polar solvents are branched or straight chained alkyl hydrocarbons having 4-10 carbon atoms and aromatic hydrocarbons having 6-20 carbon atoms especially toluene. The reaction is generally conducted with heating at reflux.
  • Step 2 the compounds of formula (IV) may be converted to the compounds of formula (I) by displacement of the leaving group, X, with a compound of formula (V), wherein R 1 and R 2 are as defined for formula (I).
  • This displacement reaction may conveniently be carried out in a solvent system, for example water, a (C1 -4) alkanol, a (C2-4) alkylene diol, 1 -hydroxy-2- methoxyethane, dimethylacetamide (DMAC), N-methylpyrolidinone, dimethyl for- mamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), toluene, dioxane or a combination of these solvents in the presence of excess amine, i.e., excess compound of formula (V), with or without a base, e.g., potassium carbonate, and/or with Nal as a catalyst.
  • a solvent system for example water, a (C1 -4) alkanol
  • This method is particularly useful for preparing compounds of formula (I) wherein R 1 is other than hydrogen.
  • a compounds of formula (II) may be converted to a compounds of formula (IIA) by displacement of the leaving group, X (as defined for Scheme I), with a compound of formula (V), wherein R 1 and R 2 are as defined for formula (I).
  • This displacement reaction may conveniently be carried out in a solvent system, for example, water, a (C1-4) alkanol, a (C2-4) alkylene diol, 1-hydroxy-2-meth- oxyethane, dimethylacetamide (DMAC), N-methylpyrolidinone, dimethyl formamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), toluene, dioxane or a combination of these solvents (to the extent of miscibility) in the presence of excess amine, i.e., excess compound of formula (V), with or without a base, e.g., potassium carbonate, and/or with Nal as a catalyst.
  • a solvent system for example, water, a (C1-4) alkanol, a (C2-4) alkylene diol, 1-hydroxy-2-meth- oxyethane, dimethylacetamide (DMAC), N-methylpyrolidinone, dimethyl formamide (DMF),
  • Step 2a General Process B
  • compound of formula (IIA) is reacted with a compound of formula (III) in a similar manner to that taught above in Scheme 1 , Step 1, to yield a compound of formula (I).
  • Step 1b a compound of formula (Va) (wherein "Hal” is halogen, i.e., fluoro, chloro, bromo or iodo) e.g., trifluoroacetamide, is reacted with a compound of for ⁇ mula (II) in a polar, aprotic solvent, e.g., acetonitrile, in the presence of a base sol ⁇ uble in the polar, aprotic solvent, e.g., cesium carbonate if the solvent is acetonitrile, to yield a compound of formula (lib).
  • a compound of formula (Va) wherein "Hal” is halogen, i.e., fluoro, chloro, bromo or iodo
  • a compound of for ⁇ mula (II) e.g., trifluoroacetamide
  • a compound of for ⁇ mula (II) e.g., triflu
  • Step 2b a compound of formula (lib) is reacted with a compound of formula (III) in a similar manner to that taught in Scheme 1 , Step 1 , to yield a compound of formula (IVb).
  • a compound of formula (IVb) is treated with an acid, H + B", such as a mineral acid, e.g., hydrochloric acid, to yield a compound of formula (lb), i.e. salt of a compound of formula (I).
  • the compound of formula (lb) may be treated with a base, such as an alkali metal hydroxide or carbonate, e.g., sodium hydroxide or potassium carbonate, by standard method of the art to yield the corresponding free base.
  • a compound of formula (lb) may be stirred with an aqueous solution of potassium carbonate for about one to about four hours in the temperature range of from about 5° to about 100°C.
  • the free base can then be converted by conventional means to a pharmaceutically acceptable salt if required.
  • the compounds of formula (II) and (III) may be prepared according to the procedure described in EPO 540 099 A1.
  • a compound of formula (I) according to the invention may be converted into another compound of the invention using conventional procedures.
  • a compound of formula (I) wherein R 1 represents a hydrogen atom may be alkylated using conventional techniques.
  • the reaction may be effected using a suitable aklylating agent such as an alkyl halide, an alkyl tosylate or a dialkylsulphate.
  • the alkylation reaction may conveniently be carried out in an organic solvent such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran, preferably in the presence of a base.
  • Suitable bases include, for example, alkali metal hydrides, such as sodium hydride, alkali metal carbonates, such as sodium carbonate, or potassium methoxide, ethoxide or t- butoxide.
  • alkali metal hydrides such as sodium hydride
  • alkali metal carbonates such as sodium carbonate
  • potassium methoxide ethoxide or t- butoxide.
  • the alkylation reaction is conveniently carried out at a temperature of from about 25 to about 100°C.
  • a compound of formula (I) wherein R 1 represents a hydrogen atom may be converted to another compound of formula (I) by reductive alkylation.
  • Reductive alkylation with an appropriate aldehyde or ketone may be effected using an alkaline earth metal borohydride or cyanoborohydride.
  • the reaction medium conveniently in an alcohol, e.g. methanol or ethanol or an ether, e.g. dioxan or tetrahydrofuran, optionally in the presence of water.
  • the reaction may conveniently be carried out at a temperature in the range of 0 to 100°C, preferably about 5 to about 50 O C.
  • a compound of formula (I) wherein R 1 represents a lower alkenyl group may be converted to another compound of formula (I) wherein R 1 represents a lower alkyl group.
  • Reduction may conveniently be effected in the presence of hydrogen and a metal catalyst, for example, Raney nickel or a nobel metal catalyst such as palladium, platinum, platinum oxide or rhodium, which may be supported, for example, on charcoal.
  • the reaction may be effected in a solvent such as an alcohol, for example ethanol and conveniently at a temperature of from about -10 to about +50°C, preferably about 20 to about 30°C.
  • a compound of formula (I) according to the invention, or a salt thereof may br prepared by subjecting a protected derivative of formula (I) or a salt thereof to reac ⁇ tion to remove the protecting group or groups.
  • the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example, “Protective Groups in Organic Chemistry” Ed. J.F.W. McOmie (Plenum Press 1973) or “Protective Groups in Organic Synthesis” by Theodora W. Greene (John Wiley and Sons 1981).
  • Conventional amino protecting groups may include, for example, aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups; and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.
  • aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl groups
  • acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl.
  • an aralkyl groups such as benzyl
  • a catalyst e.g. palladium on charcoal
  • an acyl group such as N-benzyloxycarbonyl may be removed by hydrolysis with, for ex ⁇ ample, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation
  • silicon protecting groups may be removed, for example, by treat ⁇ ment with fluoride ion or by hydrolysis under acidic conditions
  • tetrahydropyran groups may be cleaved by hydrolysis under acidic conditions.
  • a compound of the invention as a salt, for exam- pie, as an acid addition salt
  • this may be achieved by treating the free base of gen ⁇ eral formula (I) with any appropriate acid, preferably with an equivalent amount, or with creatinine sulphate in a suitable solvent (e.g. aqueous ethanol).
  • a suitable solvent e.g. aqueous ethanol
  • the general methods indicated above for the preparation of the compounds of the invention may also be used of the introduction of the desired groups at an inter ⁇ mediate stage in the preparation of the required compound. It should therefore be appreciated that in such multi-stage processes, the sequence of reactions should be chosen in order that the reacting conditions do not affect groups present in the molecule which are desired in the final product.
  • the biological activity of the compounds of formula (I) appears to reside in the S enantiomer, and the R enantiomer has little or no activity.
  • the S enan- tiomer of a compound of formula (I) is generally preferred over a mixture of R and S such as the racemic mixture.
  • the R enantiomer were desired, e.g., for control studies or synthesis of other compounds, it could be conveniently prepared by the procedure above using the R enantiomer of the compound of formula (III) prepared according to the teachings of '512.
  • a compound of formula (I) prepared by reaction Scheme I or Scheme IA may be purified by conventional methods of the art, e.g., chromatography, distillation or crystallization.
  • Table A shows the relative topoisomerase Type I inhibitory activity of the compounds of Formula (I).
  • This assay performed according to the method described in Hsiang, Y. et al., J. Bio I. Chem., 260:14873-14878 (1985), correlates well with in vivo anti-tumor activity of topoisomerase inhibitors in animal models of cancer, e.g., camptothecin and its analogs. See Hsiang et al., Cancer Research, 49:4385-4389 (1989) and Jaxel et al., Cancer Research, 49:1465-1469 (1989).
  • ICso means the concentration of a compound of formula (I) at which 50% of the DNA substrate has been captured by topoisomerase I.
  • the compounds of formula (I) are active against a wide spectrum of mammalian (including human) tumors and cancerous growths such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, rectum, liver and biliary passages, pan- creas, larynx, lung, bone, connective tissue, skin, colon, breast, cervix uteri, corpus endometrium, ovary, prostate, testis, bladder, kidney and other urinary tissues, eye, brain and central nervous system, thyroid and other endocrine gland, leukemias (lymphocytic, granulocytic, monocytic), Hodgkin's disease, non-Hodgkin's lym- phomas, multiple myeloma, etc.
  • tumors and cancerous growths such as cancers of the oral cavity and pharynx (lip, tongue, mouth, pharyn
  • the amount of compound of formula (I) required to be effective as an antitu ⁇ mor agent will, of course, vary with the individual mammal being treated and is ul ⁇ timately at the discretion of the medical or veterinary practitioner.
  • the factors to be considered include the condition being treated, the route of administration, the na ⁇ ture of the formulation, the mammal's body weight, surface area, age and general condition, and the particular compound to be administered.
  • a suitable effective antitumor dose is in the range of about 0.1 to about 200 mg/kg body weight per day, preferably in the range of about 1 to about 100 mg/kg per day.
  • the total daily dose may be given as a single dose, multiple doses, e.g., two to six times per day, or by intravenous infusion for a selected duration. Dosages above or be ⁇ low the range cited above are within the scope of the present invention and may be administered to the individual patient if desired and necessary.
  • a dose range would be about 75 to about 7500 mg per day, and a typical dose would be about 800 mg per day. If discrete multiple doses are indicated, treatment might typically be 200 mg of a compound of formula (I) given 4 times per day.
  • Formulations of the present invention for medical use, comprise an active compound, i.e., a compound of formula (I), together with an acceptable carrier therefof and optionally other therapeutically active ingredients.
  • the carrier must be pharmaceutically acceptable in the sense of being compatible with the other in ⁇ gredients of the formulation and not deleterious to the recipient therefor.
  • the present invention therefore, further provides a pharmaceutical formula- tion comprising a compound of formula (I) together with a pharmaceutically accept ⁇ able carrier thereof.
  • the formulations include those suitable for oral, rectal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Preferred are those suitable for oral or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into asso ⁇ ciation with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into desired unit dosage form.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or gran ⁇ ules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, in ⁇ ert diluents, surface active or dispersing agents.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.
  • a syrup or suspension may be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which may also be added any accessory ingredients.
  • a sugar e.g., sucrose
  • Such accessory ingredient(s) may include flavor ⁇ ing, an agent to retard crystallization of the sugar or an agent to increase the solu ⁇ bility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.
  • Formulations for rectal or vaginal administration may be presented as a sup ⁇ pository with a conventional carrier, e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany, for a suppository base).
  • a conventional carrier e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany, for a suppository base).
  • the compounds according to the invention may be formulated as creams, gels, ointments or lotions or as a transdermal patch.
  • compositions may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending and/or coloring agents.
  • Formulations suitable for parenteral administration conveniently comprise a sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient.
  • Such formulations suitably comprise a solution or suspension of a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that is isotonic with the blood of the recipient.
  • Such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline and a pharmaceutically and pharmacologically acceptable acid addition salt of a compound of the formula (I) that has an appropriate solubility in these solvents, for example the hydrochloride.
  • Useful formulations also com ⁇ prise concentrated solutions or solids containing the compound of formula (I) which upon dilution with an appropriate solvent give a solution suitable for parental ad ⁇ ministration above.
  • the formulations of this inven ⁇ tion may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.
  • room temperature means about 25°C.
  • the solid that is collected by suction filtration is purified by silica gel chromatography or reverse phase HPLC (Rainin Dynamax 60A col- umn, eluting with 2% trifluoroacetic acid in water (70-80%) and 4:1 acetonitrile THF (20-30%), monitoring at 254 nm) to afford the product amine as either the free base or the trifluoroacetic acid salt respectively.
  • silica gel chromatography or reverse phase HPLC Rainin Dynamax 60A col- umn, eluting with 2% trifluoroacetic acid in water (70-80%) and 4:1 acetonitrile THF (20-30%), monitoring at 254 nm
  • a 1-L, three-necked, round-bottomed flask was fitted with a magnetic stirring bar, thermometer, reflux condenser with calcium chloride filled drying tube, and a nitrogen inlet.
  • the reaction vessel was charged with dry methylene chloride (100 ml) and 1 ,4-benzodioxane-6-amine (15.12 g, 100 mmol).
  • the reaction vessel was cooled to 0°C followed by slow addition of 400 ml of a 1 M solution of boron trichloride in methylene chloride while maintaining an internal temperature at or below 10°C.
  • Aluminum chloride 13.34 g, 100 mmol
  • the reaction was stirred for 30 min at 0°C then heated to 40°C for 16 hours.
  • the reaction was removed from heat, allowed to cool to room temperature, then quenched into a mixture of 1 kg of ice/ 500 ml of 1N HCI. The mixture was stirred until no solids were observed.
  • the methylene chloride layer was removed and the aqueous layer was extracted twice with methylene chloride.
  • the organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, treated with decolorizing carbon, filtered through a pad of celite, and concentrated to a solid residue.
  • the solid was recrystallized from ethyl acetate/hexanes to give 8.3 g (36.5%) of 6'- amino-3',4'-ethylenedioxy-2-chloroacetophenone.
  • the solid that is collected by suction filtration is purified by reverse phase HPLC (Rainin Dynamax 60A column, eluting with 2% trifluoroacetic acid in water (70-80%) and 4:1 acetonitrile:THF (20-30%), monitoring at 254 nm) to afford the product amine as the trifluoroacetic acid salt.
  • reverse phase HPLC Rainin Dynamax 60A column, eluting with 2% trifluoroacetic acid in water (70-80%) and 4:1 acetonitrile:THF (20-30%), monitoring at 254 nm
  • the crude product is collected by suction filtration and purified by flash chromatography (eluting with 6:5:1 EtOAc/CHCl3/MeOH) to afford the amine product which was further purified by recrystallizing from f-butylmethyl ether to afford 100.6 mg (34% yield) of pure product.
  • the TLC salt was formed by dissolving in 2% aqueous trifluoroacetic acid and lyophylizing to afford the product TFA salt (141.4 mg) as a bright yellow solid, mp 280 °C (dec).
  • the solid that is collected by suction filtration is purified by reverse phase HPLC (Rainin Dynamax 60A column, eluting with 2% trifluoroacetic acid in water (70-80%) and 4:1 acetonitrile THF (20- 30%), monitoring at 254 nm) to afford the product amine as the trifluoroacetic acid salt 214 mg (68%).
  • the silicone fluid and active compound i.e., a compound of formula (I) are mixed together and the colloidal silicone dioxide is reacted with to increase viscosity.
  • the material is then dosed into a subsequently heat sealed polymeric laminate comprised of the following: polyester release liner, skin contact adhesive composed of silicone or acrylic polymers, a control membrane which is a polyolefin (e.g. polyethylene),polyvinyl acetate or polyurethane, and an impermeable backing membrane made of a polyester multilaminate.
  • the system described is a 10 sq. cm patch.
  • the active compound and the starch are granulated with water and dried. Magnesium stearate is added to the dried granules and the mixture is thoroughly blended. The blended mixture is compressed into a tablet.
  • the inactive ingredients are mixed and melted.
  • the active compound is then re ⁇ distributed in the molten mixture, poured into molds and allowed to cool.
  • the active compound and buffering agents are dissolved in the propylene glycol at about 50°C.
  • the water for injection is then added with stirring and the resulting solution is filtered, filled into an ampule, sealed and sterilized by autoclaving.
  • the finely ground active compound is mixed with the lactose and stearate and packed into a gelatin capsule.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
EP94915931A 1993-04-29 1994-04-28 Wasserloesliche camptothecinderivate und ihre verwendung als antitumormittel Withdrawn EP0696285A1 (de)

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US5458593A 1993-04-29 1993-04-29
US54585 1993-04-29
US8104293A 1993-06-22 1993-06-22
US81042 1993-06-22
PCT/US1994/004681 WO1994025466A1 (en) 1993-04-29 1994-04-28 Water soluble derivatives of camptothecin and their use as antitumor agents

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JP (1) JPH08509740A (de)
AP (1) AP9400638A0 (de)
AU (1) AU6777194A (de)
CA (1) CA2161681A1 (de)
IL (1) IL109470A0 (de)
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US6504029B1 (en) * 1995-04-10 2003-01-07 Daiichi Pharmaceutical Co., Ltd. Condensed-hexacyclic compounds and a process therefor
US5663177A (en) * 1995-05-31 1997-09-02 Smithkline Beecham Corporation Water soluble camptothecin analogs
SG103322A1 (en) * 1996-10-30 2004-04-29 Tanabe Seiyaku Co S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof
US6559309B2 (en) 1996-11-01 2003-05-06 Osi Pharmaceuticals, Inc. Preparation of a camptothecin derivative by intramolecular cyclisation
US6046209A (en) * 1997-05-27 2000-04-04 Smithkline Beecham Corporation Water soluble camptothecin analogs
IN189180B (de) * 1997-07-09 2003-01-04 Chong Kun Dang Corp
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6858598B1 (en) 1998-12-23 2005-02-22 G. D. Searle & Co. Method of using a matrix metalloproteinase inhibitor and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US6288072B1 (en) * 1999-12-29 2001-09-11 Monroe E. Wall Camptothecin β-alanine esters with topoisomerase I inhibition

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DK0418099T3 (da) * 1989-09-15 2002-04-02 Res Triangle Inst Fremgangsmåde til fremstilling af 10,11-methylendioxy-20(RS)-camptothecin og 10,11-methylendioxy-20(S)-camptothecinanaloger
EP0540099B1 (de) * 1991-10-29 1996-04-17 Glaxo Wellcome Inc. Wasserlösliche Camptothecinderivate
CA2087898A1 (en) * 1992-01-24 1993-07-25 Hiroshi Akimoto Condensed heterocyclic compounds, their production and use

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IS4152A (is) 1994-10-30
PE52894A1 (es) 1995-01-06
CA2161681A1 (en) 1994-11-10
AU6777194A (en) 1994-11-21
WO1994025466A1 (en) 1994-11-10
IL109470A0 (en) 1994-07-31
AP9400638A0 (en) 1995-10-28
MY141374A (en) 2010-04-16
JPH08509740A (ja) 1996-10-15

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