WO2010070365A1 - Hétérocycles-1,3 condensés avec un squelette monoterpénique, utilisation de ceux-ci et compositions pharmaceutiques comprenant de tels composés - Google Patents

Hétérocycles-1,3 condensés avec un squelette monoterpénique, utilisation de ceux-ci et compositions pharmaceutiques comprenant de tels composés Download PDF

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WO2010070365A1
WO2010070365A1 PCT/HU2009/000102 HU2009000102W WO2010070365A1 WO 2010070365 A1 WO2010070365 A1 WO 2010070365A1 HU 2009000102 W HU2009000102 W HU 2009000102W WO 2010070365 A1 WO2010070365 A1 WO 2010070365A1
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compounds
stands
dimethyl
undec
oxa
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PCT/HU2009/000102
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Ferenc FÜLÖP
Zsolt Szakonyi
V. Peter Pallai
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Bioblocks Magyarország Gyógyszerkémiai És Fejlesztö Kft.
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Publication of WO2010070365A1 publication Critical patent/WO2010070365A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • 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
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2

Definitions

  • the invention relates to 1,3-heterocycles condensed with monoterpene skeleton, their use and pharmaceutical compositions comprising such compounds.
  • irradion therapy beside the widely used ionizing irradiation, in special cases, e.g. with skin cancers, phototherapy and, combined with irradiation and chemotherapy, local hyperthermy are used.
  • irradion therapy when assorting according to their effect, origin or structure, alkylating agents, plant-alkaloids, antibiotics, antimetabolites, other agents (e.g. asparaginase), as well as the similarly often used various hormones are equally found.
  • Recent strategies used in chemotherapy are: combined chemotherapy; venous or arterial infusion in small doses and for long time of chemotherapeutical agents for decreasing toxicity; chemotherapy with high doses for overcoming drug resistency; the same combined with autologous marrow-transplantation; combination of chemo- therapeutical drugs and agents modifying biological response; enhanced use of adjuvant and neoadjuvant chemotherapy.
  • the most frequently used agents modifying biological response are interferons, tumor necrosis factor, limphokines, e.g. interleukin-2, and monoclonal antibodies.
  • Various dietetic methods and the use of still not cleared up serum preparations belong to methods that are used even today but do not show proved results in treating tumours.
  • WO 2007130404 describes condensed pyrrol derivatives that can be used for treating lung cancer.
  • European patent application No. 1,557,415 describes condensed pyrimidine derivatives showing anticancerous effect.
  • European patent application No. 1,631,225 discloses condensed heterocyclic compounds useable for treating skin diseases and tumours.
  • US 2005/0080096 Al describes condensed pyrimidinone, quinazolinone and phthalazinone derivatives that can be used for treating or preventing tissue damage originating from cell damage or cell decay due to necrosis or apoptosis.
  • US 7,071,189 describes pyrimidine derivatives having antitumorous effect.
  • US 7,071,218 describes pyrrole derivatives that can be used for treating metabolism disturbances and cancer.
  • US 7,129,351 describes condensed pyrimido compounds that can be used for treating breast, colon, liver and pancreas tumours.
  • the chemotherapeutic agents also show many kinds of toxic side-effects. They may damage the central nervous system, the blood-forming organs, the mucous membrane of bowel and intestines and every cells that are able to multiply. Besides, they may cause damage to liver-, kidney-, lung- and heart- muscles. All cytostatics damage the immunoreactivity of the organism [Proc. Roy. Soc. Med., 63, 1063- 1066 (1970)]. Many of them show teratogenic or carcinogenic effect, may be they cause infertility or increase the frequency of secondary tumour treatments. 60-70% of the tumours automatically cannot be or can be only difficultly influenced by chemotherapy, or resistency or cross-resistency is developed in them during treatment.
  • the inventors of the present application also have recently rendered account of the synthesis of chiral compounds of 2-arylimino-spirooxazolidine structure with monoterpenic skeleton, showing structural relationship with the above compounds [Szakonyi Z., Hetenyi A., F ⁇ l ⁇ p F., ARKIVOC part (iii), 33-42 (2008)].
  • ⁇ -pinene a natural monoterpene
  • 1,3-Oxazines that are analogous to 1,3-oxazolidines form a compound family that is interesting both from chemical and pharmacological points of view [Lazar L., F ⁇ l ⁇ p F.: 1,3-Oxazines and their Benzo Derivatives, Comprehensive Heterocyclic Chemistry III (Eds.: Katritzky A. R., Ramsden C. A., Scriven E. F. V., Taylor R. J. K.), Elsevier, Vol. 8 (Volume Ed.: Aitken A. R.), pp. 373-459 (2008)].
  • the object of the present invention is to develop novel compounds, the chirality of which derives from the natural source [(-)-mirtenale and (+)- ⁇ -pinene] as used during their preparation; besides, the compounds are readily available and need inexpensive starting materials, they show beside favourable therapeutic effect toxic effect not at all or only in a minimal degree and eliminate disadvantages of known tumour therapeutical compositions and processes, namely toxicity, specificity of small degree and small effect spectrum, and render possible prevention of tumorous deseases and, resp., stopping of division of abnormally growing cells and thereby curing of cancerous diseases.
  • the invention is based on the recognition that the novel terpene derivatives of general formula (I) render possible to attain the above object since they are non-toxic compounds of anticancerous effect that are able to kill abnormal tumour cells even in very low concentration ranges.
  • the invention relates to chiral compounds of monoterpenic skeleton of general formula (I) - where in the general formula (I) X stands for O or H 2 ; W stands for O, S, N-R 2 or Ph-R 3 ; Y stands for O or N-R 4 ; R 1 stands for H, C 1-4 AIk or (CH 2 ) 1-4 -Ph; R 2 stands for C M Alk or Ph-R 3 ;
  • R 3 stands for H, C 1 . 4 Alk, C 1-4 AIk-O or HIg
  • R 4 stands for H or Ph
  • one of the signs — means the presence of a double bond and the other means the absence of a double bond, with the proviso that only one of W and Y may simultaneously stand for oxygen — , as well as to their prodrugs and salts formed with pharmaceutically acceptable acids.
  • AIk stands for alkyl
  • HIg stands for halogen
  • Ph stands for phenyl
  • Me stands for methyl
  • Et stands for ethyl.
  • the compounds according to the invention can be used without toxic effect for preventing tumour development, for avoiding tumour-development in case of transplantation, to prevent metastases as well as to treat and cure tumorous patients in direct, adjuvant or combined way.
  • the invention also relates to the pharmaceutically accceptable salts of the above compounds.
  • the term .pharmaceutically acceptable salts relates to salts that are not toxic for living organisms. Such salts can be prepared by reacting the compounds of general formula (I) with an inorganic or organic acid. These salts often show more advantageous dissolution properties than the compounds as used for their preparation and thus they can be often used more advantageously e.g. for preparing liquid or emulsified compositions.
  • the term ,,acid addition salt relates to a salt of the compound of general formula (I) that is prepared by reacting a compound of general formula (I) with a mineral or organic acid.
  • the pharmaceutically acceptable acid-addition salts are described in detail for example in the article by S. M. Berge, L. D. Bighley and D. C. Monkhouse [J. Pharm. Sci. 66:1 (1977)].
  • the compounds according to the invention have a basic character; accordingly, they react with several inorganic or organic acid forming pharmaceutically acceptable acid-addition salts.
  • the pharmaceutically acceptable acid-addition salts according to the invention can be prepared by reacting a compound of general formula (I) with equimolar or excess amount of an acid.
  • the reagents are generally reacted in a suitable solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, isopropanol, benzene and the like.
  • the salts are usually precipitated from the solution within one-two hours but the time necessary for this precipitation can reach even 10 days.
  • the salts can be separated by filtration or any other usual method.
  • hydrochloric acid hydrobromic acid, hydrogen iodide, sulphuric acid, phosphoric acid and the like
  • organic acids useable for this purpose we mention the p-toluenesulphonic acid, methanesulphonic acid, oxalic acid, p-bromophenolsulphonic acid, tartaric acid, citric acid, benzoic acid and the like.
  • salts of the compounds of formula (I) we mention the following salts of the compounds of formula (I): sulphate, pyrosulphate, hydrogen-sulphate, sulphite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formiate, isobutyrate, caproate, heptanoate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, metoxybenzoate, phthalate, sulphonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, /3-hydroxy butyrate, tartarate, methanesulphonate,
  • the compounds of formula (I) contain one or more asymmetry centre and thus they exist as enantiomers or diastereoisomers.
  • the invention comprises both the mixtures and the separate isomers.
  • the compounds of general formula (I) also exist in tautomeric forms, and the invention comprises both the mixtures and the separate tautomers.
  • the compounds of general formula (I) and their salts may also exist in the form of solvates which also fall under the scope of the invention.
  • the solvate preferably comprises a hydrate or an ethanolate.
  • the invention also relates to radiolabelled derivatives of compounds of general formula (I) which can be used for biological studies.
  • the invention also relates to processes of preparation of compounds of general formula (I).
  • reaction scheme 1 For preparing the compounds according to the invention one proceeds according to reaction scheme 1 in the following way. ai) The synthesis of 4-pyrimidinones is carried out by melting suitable azetidinones with aryl imidates without organic solvent, at higher temperatures. Detailed experimental description and the features of the prepared compounds are given in Examples 1 and 2. a 2 ) The compounds can be also prepared by reacting the suitable amino acid esters and arylimidates in ethanol at higher temperatures.
  • the first step of synthesis of 2,4-pyrimidinediones and 2-thioxo-4-pyrimidinones is carried out by condensing amino acid esters and corresponding isocyanates and, resp., isothiocyanates in an organic solvent. Following evaporation the intermediate product is boiled with aqueous hydrochloric acid solution. The synthesis is carried out by starting from ethyl-(l/?,2/?,35,5 ⁇ )-2-amino-6,6-dimethyl- bicyclo[3.1.1]heptane-3-carboxylate of formula 4. The detailed experimental description and the features of the prepared compounds are given in Examples 3 and 4.
  • the first step of the synthesis of 2-alkyl- and, resp., 2-arylamino-l,3-oxazines can be carried out by condensing the suitable aminoalcohols and suitable alkyl- and, resp., arylisotbiocyanates in an organic solvent. After evaporation the intermediate product is stirred at room temperature in a methanolic methyl iodide solution and then in a methanolic potassium hydroxide solution. Detailed experimental description and features of the prepared compounds are given in Examples 5 to 17.
  • the invention also relates to the preparation of anticancerous pharmaceutical compositions comprising compounds of general formula (I) or their salts. According to the invention one proceeds by mixing one or more compounds or salts of general formula (I) with usual inert pharmaceutical carriers and/or auxiliary agents to anticancerous pharmaceutical compositions.
  • the invention relates to the use of one or more compounds of general formula (I) and/or the salts of such compounds for preparing anticancerous pharmaceutical compositions.
  • the invention also provides a method for treating and/or curing cancerous illnesses which comprises administering an effective amount of the pharmaceutical composition according to the invention to a patient in need of such treatment.
  • treatment is used here in the usual sense, that is it relates to prevent, hinder, improve, suppress or slow down the cancerous disease or to decrease the gravity of the illness.
  • the compounds of general formula (I) according to the invention are administered in solid, liquid or spray form alone or in combination with one or more usual pharmaceutical carrier or auxiliary agent.
  • the invention comprises also pharmaceutical compositions which comprise an effective amount of compounds of general formula (I) together with a pharmaceutically acceptable carrier.
  • the compounds according to the invention can be also administered together with other anticancerous agents, too.
  • solid carriers useable in the compositions according to the invention one or more agents can be used that simultaneously serve as sliding, solubilizing, suspending, binding, filling, pressing, disintegrating, flavouring or encapsulating agents.
  • the carrier can be a finely divided solid material that is mixed with finely divided particles of compounds of general formula (I).
  • the compound of general formula (I) is mixed in suitable ratios with a carrier that has the required pressing properties, and the mixture is pressed to the desired form and size.
  • the above-mentioned powders and tablets contain the compound of general formula (I) in an amount ranging up to 99% by mass.
  • compositions of spray form are generally used as aerosol compositions for absorption by the skin surface or through the lungs.
  • solid carriers that can be used in the compositions according to the invention we mention the talc, calcium phosphate, magnesium stearate, lactose, dextrin, starch, gelatine, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and waxes of low melting point.
  • any pharmaceutically acceptable liquid carrier can be used which is suitable for preparing solutions, suspensions, emulsions, syrups and therapeutical drinks.
  • the compounds of general formula (I) can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, organic solvents, or pharmaceutically acceptable oils or fats or a mixture thereof.
  • a pharmaceutically acceptable liquid carrier such as water, organic solvents, or pharmaceutically acceptable oils or fats or a mixture thereof.
  • the said liquid composition may contain other suitable pharmaceutical additives such as solubilizing agents, emulsifying agents, buffers, conserving agents, sweeteners, flavouring agents, suspending agents, thickeners, colouring agents, viscosity regulators, stabilizers, osmotic pressure regulators and the like.
  • liquid carriers for oral or parenteral administration the following examples of liquid carriers are mentioned: water solutions containing additives such as cellulose derivatives, preferably sodium carboxymethylcellulose, alcohols including primary and secondary alcohols such as glycols, alcohol derivatives or oils such as fractionated coconut oil and arachis oil.
  • additives such as cellulose derivatives, preferably sodium carboxymethylcellulose, alcohols including primary and secondary alcohols such as glycols, alcohol derivatives or oils such as fractionated coconut oil and arachis oil.
  • the carrier oil can be an ester such as ethyl oleate or isopropyl myristate.
  • compositions according to the invention can be liquid or solid.
  • compositions according to the invention that are sterile solutions or suspensions can be used as intramuscular, intraperitoneal or subcutaneous injections.
  • the sterile solutions can be administered intravenously, too.
  • the compounds according to the invention can be formulated together with pharmaceutically active other substances.
  • the choice of such materials depends on the aim of using the composition.
  • the concentration of compounds of general formula (I) depends on several factors such as method of administration, chemical nature of the compounds, state and clinical indication of the patient. Therefore, the concentration can vary in a wide range.
  • the concentration of the active agent can be 0.002-99% by mass, for example 0.01-70% by mass, preferably 0.05-40% by mass, more preferably 0.1-20% by mass.
  • a composition according to the invention can be administered enterally, parenterally, locally, rectally or systemicly, depending on the prescription and the active agent used, e.g. in the form of tablets, capsules, powders, granules, syrup, spray, or injection solution.
  • compositions for enteral administration can be for example powders, simple or coated tablets, tablets with protracted effects, soft capsules, hard capsules, rectal suppositories, suspensions and solutions which, if desired, may contain the active agents together with one or more usual carriers.
  • compositions for parenteral administration can be e.g. preparations for intradermal, subcutaneous, intraperitoneal or intravenous injections or infusions.
  • Other parenteral compositions can be applied not only on the skin but also on the mucous membrane.
  • Such local compositions can be e.g. gels, creams, ointments, shampoos, soaps, sprays, rinsing agents, smears, aerosols, and other pharmaceutical preparations suitable for local administration.
  • the compounds according to the invention preserve their effect when used in any form, e.g. when used in the usual oral, rectal or injection form.
  • the daily dose of the compounds according to the invention amounts for adults to 200-1000 mg, preferably 50-500 mg, more preferably 20-100 mg. These doses can be increased or decreased depending on the state of the patients.
  • the acute oral toxicity test of the compounds according to the invention in cornseed-oil on female mice proved that the compounds are not toxic in a daily dose of 2000 mg/kg.
  • the (1S,5S)- and (lR,5R)-apopinene (b and e) serving as starting compounds for preparing the compounds according to the invention were synthesised according to literature methods, in the way as shown in the enclosed reaction scheme 2 [Shibuya K., Synth. Commiin., 24, 2923-2941 (1994); Lightner,
  • reaction schemes 3-8 When describing the syntheses of the compounds according to the invention we refer to reaction schemes 3-8.
  • reaction scheme 3 the preparation of 4-pyrimidinones is shown, starting from chiral azetidinones of formula 1.
  • reaction scheme 4 the preparation of 2,4-pyrimidinediones and 2-thioxo-4-pyrimidinones is shown, starting from aminocarboxylic esters of formula 4.
  • reaction schemes 5-8 the preparation of 1,3-oxazines condensed with monoterpenes is shown, starting from aminoalcohols of formulae 7a-c, 14, 16 and 18.
  • Schemes 1 to 8 are illustrated in Fig. 1 in the enclosed drawing.
  • the reactions are followed by thin-layer chromatography.
  • the working up can be carried out by evaporation or extraction.
  • the product can be purified by crystallization or chromatography.
  • the structure and purity of compounds is proved and, resp., controlled by NMR spectroscopy, melting-point measurement and/or CHN microanalyses.
  • the enantiomeric purities of the prepared compounds were determined by means of GC measurements involving direct separation of the enantiomers on a CHIRASIL-DEX CB column (2500x0.25 mm I.D.) at 160 0 C and 80 kPa for azetidinones. IR spectra were measured with a FT-IR spectrometer.
  • Example 6a 25 according to Example 6a, was stirred in solution of 10% hydrochloric acid in dry ethanol (20 ml) at room temperature. After 1.5 h stirring the solution was evaporated to dryness and the crystalline product obtained was recrystallized from diisopropyl ether/ethyl acetate mixture.
  • Example 17 (15 l ,25,75,95)-(10,10-Dimethyl-5-oxa-3-azatricyclo[7.1.1.0 2 ' 7 ]undec-4-ylidene)phenylainine (compound 19) (Scheme 8) a) (15,25,5 ⁇ ,75)-8,8-Dimethyl-3-a2atricyclo[5.1.1.0 2 ' 5 ]nonan-4-one
  • the cytostatic effect of the compounds according to the invention was evaluated in vitro in a concentration range of 3-90 ⁇ M on three human tumour cell lines (A431, HeLa, MCF7*). * A431 : human squamosus carcinoma HeLa: human cervix adenocarcinoma MCF7: human breast adenocarcinoma.
  • the cytostatic MTT-assay is a widely used antiproliferative method in which the test compounds are screened for cytostatic property [Sobottka, S. B. and Berger, M. R.: Cancer Chemotherapy and Pharmacology 30, 385-393 (1992)].
  • This test is a highly reproducible and high-throughput method carried out on 96-well microplates. A limited amount of human cancer cells (5000/well) was seeded onto the microplate. During an overnight preincubation period the cells sedimented on the bottom of the well. On the second day of the test the original medium was removed and 200 ⁇ l of a new medium containing the test substances in a final concentration of 3-90 ⁇ M were added.
  • a 30 ⁇ M stock solution of each compound to be tested was prepared with dimethyl sulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • the final DMSO concentration of the medium was never higher than 0.3% by mass since this value has no substantial background effect on cell proliferation.
  • MTT is a yellowish dye which was converted by intact mitochondrial reductase and precipitated as blue crystals during a 4-hour contact period.
  • the medium was removed and the precipitated crystals were dissolved in 100 ⁇ l of DMSO during a 60-minute period of shaking.
  • the reduced MTT was determined at 550 run using a microplate reader. The absorbance values were compared to values obtained for control wells containing only medium. AU in vitro experiments were carried out on two microplates with at least 5 parallel wells.
  • cytostatic effect of compounds 8a, 9a, 9b, 10a, 11a, 12a, 15, 17, and 19 was assayed in a concentration range of 3 to 90 ⁇ M.
  • Sigmoidal curves were fitted on the results and the IC 50 values, that is the concentration of the tested compounds at which 50% of the maximal cytostatic effect could be detected, were calculated by GraphPad Prism 2.01 method.
  • the thus-obtained diagrams are presented for compounds 9a, 9b, 10a, 1 Ia, 12a and 17 on the enclosed drawing (Figs 3 to 5).
  • the inhibiting effect (ID 50 ) of the compounds according to the invention exerted on cancerous cells was tested on six tumour cell lines.
  • the compounds were tested at 10 ⁇ M concentration, by a 72 h treatment after 16 h preincubation on the following cell lines: U937 human leukemic monocyte lymphoma
  • the cell number was 2000/well in 100 ⁇ l RPMIl 640+FBS/well, on 96well PerkinElmer black culture plates (#6005668).
  • Score is calculated as the sum of the mean viability values of different cell lines. Score above 400 means that the drug had no significant effect, score below 400 and above 200 means that efficiency is significant (33% average growth inhibition on all cell lines), and score below 200 means that the drug has more than 66% average growth inhibitory effect on the cell lines.
  • the compounds were tested at 1 ⁇ M, 2 ⁇ M, 5 ⁇ M, 10 ⁇ M, and 20 ⁇ M concentration according to the protocol under item Bl).
  • Data processing highest and lowest data from 5 parallels were excluded. Mean values, average and standard deviations were calculated from the 3 remaining data. Viability values are calculated in percentage, they correlate to the mean control value of 100.

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Abstract

La présente invention concerne des composés chiraux dotés d'un squelette monoterpénique de formule générale (I). Dans ladite formule, X représente O ou H2 ; W représente O, S, N-R2 ou Ph-R3 ; Y représente O ou N-R4 ; R1 représente H, C1-4Alk ou (C2)1-4-Ph ; R2 représente C1-4Alk ou Ph-R3 ; R3 représente H, C1-4Alk, C1-4Alk-O ou Hlg ; R4 représente H ou Ph ; et l'un des signes --- implique la présence d'une double liaison et l'autre implique l'absence d'une double liaison, à la condition que W ou Y puisse représenter simultanément un oxygène. L'invention porte en outre sur leurs promédicaments et sur leurs sels formés avec des acides pharmaceutiquement acceptables. En outre, l'invention concerne des compositions pharmaceutiques cytostatiques comprenant un ou plusieurs composés de formule générale (I) et des porteurs pharmaceutiques inertes habituels et/ou des agents auxiliaires. L'invention porte également sur l'utilisation de ces composés de formule générale (I) dans la préparation de compositions pharmaceutiques cytostatiques ainsi que sur le traitement et/ou la guérison de maladies cancéreuses.
PCT/HU2009/000102 2008-12-18 2009-12-10 Hétérocycles-1,3 condensés avec un squelette monoterpénique, utilisation de ceux-ci et compositions pharmaceutiques comprenant de tels composés WO2010070365A1 (fr)

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