WO2017103637A1 - Diphenylpropane compounds and their cytotoxic activity - Google Patents

Diphenylpropane compounds and their cytotoxic activity Download PDF

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WO2017103637A1
WO2017103637A1 PCT/IB2015/002409 IB2015002409W WO2017103637A1 WO 2017103637 A1 WO2017103637 A1 WO 2017103637A1 IB 2015002409 W IB2015002409 W IB 2015002409W WO 2017103637 A1 WO2017103637 A1 WO 2017103637A1
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amg
propoxybenzo
methoxyphenyl
dioxo
oxathiol
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PCT/IB2015/002409
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French (fr)
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Marek Konieczny
Andrzej SKŁADANOWSKI
Krzysztof Lemke
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Blirt S.A.
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Publication of WO2017103637A1 publication Critical patent/WO2017103637A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/04—Five-membered rings

Definitions

  • the invention relates to new derivatives of 1,3-diphenylpropane that from a chemical point of view can be considered as derivatives of chalcone with various degree of reduction of the enone system, to pharmaceutical compositions containing the same, and to their use in therapy of cancer related diseases.
  • Chalcones can be defined as compounds composed of two phenyl rings connected with a propen-3-one unit. They belong to the class of unsaturated aromatic ketones and are known as by-products in biosynthesis of flavonoids. In the prior art, various chalcone derivatives are disclosed, displaying diverse biological activity, including antiinflammatory, anticancer or antibacterial.
  • WO03/048106 various chalcone derivatives substituted in both rings with substituents like OH, OCH 3 , F, CI, Br, SCH 3 , CF 3 , NH 2 , NR 2 , and displaying anticancer activity are known.
  • WO03/076407 discloses derivatives of l-(4-methoxyphenyl)-3-(3,5-dimethoxyphenyl)prop- l-en-3-one possessing anticancer and antiangiogenic activity.
  • Publication WOl 1/009826 discloses derivatives of chalcone with anticancer activity wherein one of the phenyl rings is fused with oxathiole, oxathiine, dioxole or dioxane ring.
  • the enone group while necessary for cytotoxic activity, can lead, in case of eventual application of chalcones as anticancer drugs, to severe side effects, related to reactions of the reactive enone moiety with nucleic acids or proteins.
  • Such interactions can effect synthesis of DNA, enzymes activations, regulations of cell cycle, and other processes vital for normal functions of organism (P. Perjesi i inn. souComparison of effects of some cyclic chalcone analogues on selected mitochondrial functions" Pharmazie 63 (2008) 899-903; P. Perjesi i inn. (E)-2- Benzylidenebenzocyclanones: Part VII. Investigation of the conjugation reaction of two cytotoxic cyclic chalcone analogues with glutathione: an HPLC-MS study" Monatsh. Chem. 143 (2012) 1107-1114).
  • Reduced derivatives of chalcone do not have the enone moiety responsible for the potentially unfavorable side effects, and it can be expected that they will exhibit much less of the undesired side effects than their analogs with unmodified enone group.
  • the present invention solves the presented above problems providing new anticancer compounds that do not lead to the undesired side effects and retain high, at nanomolar level activity.
  • the invention relates to new derivatives of 1,3-diphenylpropane of general formula (I), and their pharmaceutically acceptable salts,
  • a and B are linked together and form a a moiety selected from -0-(CH 2 ) n -S(0) m -, -S(0) m -
  • R is H, Ci-Ce-alkyl, CO-Ci-C 6 -alkyl, or -(CH 2 ) P -NR 1 R 2 , wherein
  • R 1 and R 2" are independently of each other, H, Ci-C 6 -alkyl, or
  • R 1 and R 2" are linked together by a polymethylene linker -(CH 2 ) q -, to form along with the nitrogen atom to which they are attached, a five or six- membered ring, wherein one of carbon atoms may be optionally replaced by O, N, or S.
  • Y is: O, H, OH, NH 2
  • derivatives of 1,3-diphenylpropane are compounds of formula (IA)
  • derivatives of 1,3-diphenylpropane are compounds of formula (IB)
  • derivatives of 1,3-diphenylpropane are compounds of formula (IC)
  • derivatives of 1,3-diphenylpropane are compounds of formula (ID)
  • derivatives of 1,3-diphenylpropane are compounds of formula (IIA)
  • derivatives of 1,3-diphenylpropane can presented by formula (IIC)
  • derivatives of 1,3-diphenylpropane are compounds of formula (IID)
  • derivatives of 1,3-diphenylpropane are compounds of formulas IIA1 - IIA4; IIB 1 - IIB4; IIC1 - IIC4; IID1 - IID4, wherein R, m, have the same meanings as defined for general formula (I).
  • derivative of 1,3-diphenylpropane is compound of formula (III)
  • A, B, R, Y have the same meanings as defined for general formula (I)
  • X is H, halogen atom, OH, -0-Ci-C 6 alkyl, -0-CO-Ci-C 6 alkyl, -0-Ci-C 6 alkyl(N(Ci-C 6 alkyl) 2 ), O- PO(OH) 2 , N0 2 , NH 2 or NHR 3 , wherein R 3 is Ci-C 6 alkyl.
  • A, B, R have the same meanings as defined for general fomiula (I)
  • X is H, halogen atom, OH, -0-Ci-C 6 alkyl, -0-CO-Ci-C 6 alkyl, -0-Ci-C 6 alkyl(N(Ci-C 6 alkyl) 2 ), 0-PO(OH) 2 , N0 2 , NH 2 or NHR 3 , wherein R 3 is Ci-C 6 alkyl.
  • derivatives of 1,3-diphenylpropanes can be presented by formulas VA-VD, VIA-VID, VIIA-VIID, VIIIA-VIIID:
  • R and m have the same meanings as defined for general formula (I)
  • X is H, halogen atom, OH, -0-Ci-C 6 alkyl, -0-CO-Ci-C 6 alkyl, -0-Ci-C 6 alkyl(N(Ci-C 6 alkyl) 2 ), O- PO(OH) 2 , N0 2 , NH 2 or NHR 3 , wherein R 3 is Ci-C 6 alkyl .
  • R is Ci-C 4 -alkyl group, particularly ethyl and propyl group.
  • halogen relates to a substituent selected from CI, F, and Br.
  • Compounds of general formula (I), having -0-PO(OH) 2 group may form salts with bases.
  • the salts also constitute a subject of the invention.
  • the invention includes sodium, potassium and lithium salts of compounds of general formula (I).
  • Salts with acids may be pharmaceutically acceptable salts, especially in case they are intended to be used as component of pharmaceutical composition.
  • the invention encompasses also salts with other than pharmaceutically acceptable acids that may be applied for example, as intermediate products in purification of compounds according to the invention.
  • Addition salts with acids my be formed with inorganic (mineral) acids or with organic acids.
  • the hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, succinic, maleic, formic, acetic, glutaminic, asparaginic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethane sulfonic, naphtalenesulfonic such as 2-naphtalenesulfonic, or hexanoic acid can be listed.
  • Addition salt with acid may be produced by reaction of compound of general formula (I) with a suitable inorganic or organic acid, ewentually in a suitable solvent, such as an organic solvent, usually the formed salt is isolated by crystallization and filtration.
  • a suitable solvent such as an organic solvent
  • free bases of compounds can be transformed into related hydrochlorides by reaction of solution of the compounds, for example in methanol, with a suitable amount of hydrochloric acid or its solution in methanol, ethanol, or diethyl ether, and evaporation of the solvents.
  • free bases of compounds can be tansformed into related methanesufonates by addition of a suitable amount of methanesulfonic acid in methanol, ethanol or diethyl ether sulution to a solution of the compound, and subsequent evaporation of solvents or precipitation of the product.
  • Pharmacological properties of the compounds according to the invention depend to much extend on possibility of their transformation into pro-drugs.
  • Compounds of general formula (I) may form pharmaceutically acceptable esters and amides that can be used as pro-drugs. The simplest effect that can be achieved in result is water solubility.
  • Derivatives substituted with hydroxyl group can be transformed into esters with phosphoric acid (compound AMG- 414), and compounds with amino group into amides of amino acids (compounds AMG-415, AMG-421).
  • Compounds according to the invention can form in case of phenol group carbamates, and in case of an amino group derivatives with other amino acids.
  • pro-drug relates to a compound that is transformed in vivo into the parent drug, in result of particular physiological processes (for example the parent drug is formed under influence of enzymes or physiological pH).
  • Pro-drugs are needed, as under some circumstances, they can be applied easier than the parent drug.
  • Pro-drug can have better than the parent drug solubility in pharmaceutical compositions, for example the pro-drug may have better water solubility, what facilitate an intravenous apllication of the drug.
  • Pro-drug may have a better bioavailability in per-os application. After application, the pro-drug is enzymatically or chemicaly cleaved, to give the parent drug in blood or other tissues.
  • Exemplary pro-drugs of compounds according to the invention include compounds wherein a hydrogen atom of amine or hydroxy group of the parent drug is replaced by a moiety such as (Ci-C 6 )alkanoiloxymethyl, l-((Ci-C 6 )alkanoiloxy)ethyl, l-methyl-l-((Ci- C 6 )alkanoiloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkanoiloxymethyl, l-((Ci-C 6 )alkanoiloxy)ethyl, l-methyl-l-((Ci- C 6 )alkanoiloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C 6 )alkanoiloxymethyl, l-((Ci-C 6 )alkanoiloxy)ethyl, l-methyl-l-
  • a-aminoacyl groups are independently selected from any natural, existing in proteins L-amino acids, -P(0)(OH) 2 , -P(0)(0(Ci-C 6 )alkyl) 2 or glycoside (a radical formed by elimination of hydroxy group from a hemiacetal form of carbohydrate).
  • the invention relates also to pharmaceutical compositions containing compounds described by the formula (I), and pharmaceutically acceptable excipient, such like vehicle.
  • the term "pharmaceutically acceptable vehicle” relates to any vehicle used in preparation of a desired pharmaceutical dosage form.
  • the pharmaceutically acceptable vehicle can include one or more solvents, diluents or other liquid disperging agents, additives used to prepare dispersion or suspension, detergents, isotonic agants, binders, emulgants, preservatives, lubricants and others.
  • Remington's Pharmaceutical Sciences, XV-th Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, III- rd Ediition, A. H. Kibbe ed. disclose various vehicles used in pharmaceutical compositions and known procedures for their preparation.
  • the invention relates also to compounds described by the above formulas for use as medicaments.
  • Subsequent invention relates to compounds described by the above formulas for use in treatment of cancer.
  • thiols are involved in regulation of redox equilibrium of cell, and its destabilizations may results in destabilization of synthesis of DNA, affects activation of enzymes, selectivity of genes expression, and regulation of cell cycle (P. Perjesi et al (Monatsh Chem (2012) 143: 1107-1114). Elimination of the double bond from the chalcone molecule resulted in elimination of possibility of reaction with the protein derived thiol groups, and subsequently in elimination of eventuall undesired side effects.
  • A, B, R, X have the same meanings as defined for a related compound (IIA), with hydrogen, in a presence of a catalyst.
  • the reaction is performed by stirring a mixture, for example of solution of a suitable chalcone in solvent like ethyl acetate, in the presence of a catalyst such as palladium on charcoal, under atmosphere of hydrogen, at room temperature, until chromatographic analysis demonstrate that the substrate have reacted completely.
  • a catalyst such as palladium on charcoal
  • Derivatives of 1,3-diphenylpropane of formulas VA to VD and VIIIA to VIIID, wherein R and m have the same meanings as defined above for formula (I), and X is -0-PO(OH) 2 , and their salts with alkali metals, may by obtained from related compounds of general formula (I), wherein X is OH, by reaction with phosphorous oxychloride P(0)C1 3 or by an alternative methods described in the state of the art for similar derivatives of phenol.
  • the catalyst is filtered off, and the filtrate is evaporated to dryness. The residue is crystallized from a suitable solvent or purified on silica gel chromatographic column, to give the product.
  • a suitable starting compound, prepared according to the procedure described above, is condensed with a suitable derivative of amino acid with protected amino group, using generally known procedures, for example condensation in a presence of dicyclohexylcarbodiimide in methylene chloride solution.
  • the obtained product is purified using column chromatography on silica gel column or is crystallized from a suitable solvent.
  • the obtained conjugate is deprotected using generally known methods, for example, deprotection of t-butylcarbamoyl group is carried out with a solution of trifluoroaeetie acid in methylene chloride.
  • the obtained product is purified using chromatography on silica gel column or by crystallization from a suitable solvent.
  • the obtained product is treated with a protic acid to give a suitable salt.
  • Trifluoroacetic acid (2 ml) was added to a solution of (S)-tert-butyl l-(2-methoxy-5-(3-oxo- 3-(3,3-dioxo-5-propoxybenzo[ ⁇ i] [l,3]oxathiol-6-yl)propyl)phenylamino)-4-methyl- l- oxopentan-2-yl carbamate (500 mg, 0,81 mmol) in anhydrous methylene chloride (10 ml), and the mixture was stirred at room temperature for 2 hours.
  • the obtained solution was poured into a stirred solution of sodium bicarbonate in ice cooled water, and the resulted mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with sodium bicarbonate solution (1 x 10 ml), brine (1 x 50 ml), and dried (Na 2 S0 4 ).
  • Suitable starting compound prepared as described above in Examples 1 - 4, is reduced using generally known methods, for example reduction with zinc in acetic acid solution, or reduction with sodium borohydride or its derivative in a solution in protic solvent.
  • the obtained product is purified using silica gel column chromatography, or by crystallization from a suitable solvent.
  • H, H-2 3,72 (s, 3 H, OCH 3 ), 2,56 (m, 2 H, H-c), 1,83 (m, 1 H, H-b), 1,67 (m, 2 H, CH 2 ),
  • a suitable starting compound, prepared as described above in Examples 7 - 10, is reduced with a reducing agent, which is suitable for reduction of nitro group, using procedures generaly known in the state of the art, and the obtained product is isolated using generaly known methods.
  • a reducing agent which is suitable for reduction of nitro group
  • the substrate is dissolved in an organic solvent, such as ethyl acetate and reacted with hydrogen in the presence of palladium catalyst, and the obtained product is isolated on silica gel chromatography column.
  • a side product in synthesis of AMG-434 (above) formed in case of prolonged zinc reduction, (2S)-2-acetamido-N-(5-(3-amino-3-(3,3-dioxo-5-propoxybenzo[ ⁇ i][l,3]oxathiol- 6-yl)propyl)-2-methoxyphenyl)-4-methylpentanamide.
  • MTT assay is a colorimetric assay used for estimation of cells proliferation and viability as well as cytotoxicity of the substance, for the cells. It consists in decomposition of the yellow tetrazolium salt MTT (methyl 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazole bromide) to insoluble in water purple dye formazan, by the mitochondrial succinic-tetrazole reductase. MTT reduction occurs in living cells only. Data analysis consists in determination of concentration of the test compound wherein 50 % reduction in the number of cells in the treated population occurs, in comparison to to the control cells. Results were analyzed using GraphPad Prism 4.0.
  • Human cervix carcinoma cells HeLa (ATCC# CCL-2) were maintained in MEM medium (HyClone, Logan, UT, USA) supplemented with 10 % fetal calf serum (HyClone, Logan, UT, USA), 2mM L-glutamine and antibiotics (penicillin 100 U/ml and streptomycin 100 mg/ml (HyClone, Logan, UT, USA) at temperature 37 °C, under atmosphere of air supplemented with 5 % of C0 2 .
  • HCT-116 Human colonic epithelial cells HCT-116 (ATCC# CCL-247) were maintained in McCoy's medium (HyClone, Logan, UT, USA) supplemented with 10 % fetal calf serum (HyClone, Logan, UT, USA), 2mM L-glutamine and antibiotics (penicillin 100 U/ml and streptomycin 100 mg/ml (HyClone, Logan, UT, USA) at temperature 37 °C, under atmosphere of air supplemented with 5 % of C0 2 .
  • Human lung adenocarcinoma epithelial cells A549 were maintained in RPMI1640 medium (HyClone, Logan, UT, USA) supplemented with 10 % fetal calf serum (HyClone, Logan, UT, USA), 2mM L-glutamine and antibiotics (penicillin 100 U/ml and streptomycin 100 mg/ml (HyClone, Logan, UT, USA) at temperature 37 °C, under atmosphere of air supplemented with 5 % of C0 2 .
  • the cells culture was diluted with the medium to a specified density (10 4 - 10 5 cells per 100 ⁇ ). Then 100 ⁇ of appropriately diluted cell suspension was applied in 96-well plate in triplicates, The cells thus prepared were incubated for 24 hours at 37 °C in 5 % C0 2 , then to the cells (in 100 ⁇ of medium) another 100 ⁇ of culture medium containing different concentrations of test compounds was added. The cells were incubated with tested compounds for subsequent 72 hours, what corresponds to 3 - 4 times of cell division. Then to the medium with test compounds 20 ⁇ of MTT working solution [5 mg/ml] was added and incubated for 3 hours at 37 °C in 5 % C0 2 .
  • Table 2 presents evaluation of anticancer activity of compound AMG-415 against murine Colon 26 carcinoma, inoculated subcutaneously to BALB/C mice.
  • Table 3 presents evaluation of anticancer activity of compound AMG-432 against murine Colon 26 carcinoma, inoculated subcutaneously to BALB/C mice.
  • AMG-412 > 4 > 4 AMG-433 0.179 0.192

Abstract

The invention relates to new derivatives of 1,3-diphenylpropane described by general formula (I), demonstrating cytotoxic activity against cancer cells, to be used as drugs in anticancer therapy, and characterized by reduced undesired side effects in comparison to related derivatives of chalcones.

Description

DIPHENYLPROPANE COMPOUNDS AND THEIR CYTOTOXIC ACTIVITY
The invention relates to new derivatives of 1,3-diphenylpropane that from a chemical point of view can be considered as derivatives of chalcone with various degree of reduction of the enone system, to pharmaceutical compositions containing the same, and to their use in therapy of cancer related diseases.
Chalcones can be defined as compounds composed of two phenyl rings connected with a propen-3-one unit. They belong to the class of unsaturated aromatic ketones and are known as by-products in biosynthesis of flavonoids. In the prior art, various chalcone derivatives are disclosed, displaying diverse biological activity, including antiinflammatory, anticancer or antibacterial.
From publications WO01/72980, W099/22728, WO99/00114, W098/58913, W091/17749, WO03/048106 various chalcone derivatives substituted in both rings with substituents like OH, OCH3, F, CI, Br, SCH3, CF3, NH2, NR2, and displaying anticancer activity are known. WO03/076407 discloses derivatives of l-(4-methoxyphenyl)-3-(3,5-dimethoxyphenyl)prop- l-en-3-one possessing anticancer and antiangiogenic activity. Publication WOl 1/009826 discloses derivatives of chalcone with anticancer activity wherein one of the phenyl rings is fused with oxathiole, oxathiine, dioxole or dioxane ring.
In the prior art, an opinion prevails that the presence of enone group is necessary for cytotoxic activity of chalcones, as its reduction results in one - two orders decrease in activity. (E. Venkateswararao et al., A SAR study on a series of synthetic lipophilic chalcones as Inhibitor of transcription factor NF- κΒ; Eur. J. Med. Chem. 54 (2012) 379- 386; D. Maydt et al., Chemical reactivity and biological activity of chalcones and other α,β- unsaturated carbonyl compounds: Xenobiotica 43(8) (2013) 711-718). The enone group, while necessary for cytotoxic activity, can lead, in case of eventual application of chalcones as anticancer drugs, to severe side effects, related to reactions of the reactive enone moiety with nucleic acids or proteins. Such interactions can effect synthesis of DNA, enzymes activations, regulations of cell cycle, and other processes vital for normal functions of organism (P. Perjesi i inn.„Comparison of effects of some cyclic chalcone analogues on selected mitochondrial functions" Pharmazie 63 (2008) 899-903; P. Perjesi i inn. (E)-2- Benzylidenebenzocyclanones: Part VII. Investigation of the conjugation reaction of two cytotoxic cyclic chalcone analogues with glutathione: an HPLC-MS study" Monatsh. Chem. 143 (2012) 1107-1114).
For the above reasons, in spite of existence of numerous known chalcone derivatives bearing cytotoxic activity, there is still a need for new derivatives of chalcones with cytotoxic activity against cancer cells that can extend our arsenal of anticancer drugs, but at the same time will be free of undesired side effects present in currently available chemotherapies.
Reduced derivatives of chalcone do not have the enone moiety responsible for the potentially unfavorable side effects, and it can be expected that they will exhibit much less of the undesired side effects than their analogs with unmodified enone group. However, the known applications of the reduced derivatives of chalcone do not suggest their use as cytotoxic agents, as they are known as antiarrhythmic drugs (for example Propafenon, Diprafenon, Alprafenon) or as artificial sweeteners, used on a large scale in food industry (neohesperidine dihydrochalcone = additive E959).
The present invention solves the presented above problems providing new anticancer compounds that do not lead to the undesired side effects and retain high, at nanomolar level activity.
It was unexpectedly found that some derivatives of 1,3-diphenylpropane display cytotoxic activity against cancer cells, similar to the activity of the analogous chalcones. At the same time, due to the lack of the reactive enone moiety, it can be expected that side effects associated with application of the cytostatic agents to patients, will be minimized, in comparison with effects of the analogous chalcones.
The invention relates to new derivatives of 1,3-diphenylpropane of general formula (I), and their pharmaceutically acceptable salts,
Figure imgf000003_0001
(I)
wherein:
A and B are linked together and form a a moiety selected from -0-(CH2)n-S(0)m-, -S(0)m-
(CH2)„-0- or -0-(CH or one of A and B is -S(0)m-Ci-C6-alkyl, and the second is selected from a group consisting of OH and -0-Ci-C6-alkyl;
R is H, Ci-Ce-alkyl, CO-Ci-C6-alkyl, or -(CH2)P-NR1R2, wherein
R 1 and R 2" are independently of each other, H, Ci-C6-alkyl, or
R 1 and R 2" are linked together by a polymethylene linker -(CH2)q-, to form along with the nitrogen atom to which they are attached, a five or six- membered ring, wherein one of carbon atoms may be optionally replaced by O, N, or S.
Y is: O, H, OH, NH2
1 2 3 are, independently of each other, H, halogen atom, OH, -0-Ci-C6alkyl, -O-CO- Ci-C6alkyl, -0-Ci-C6alkyl(N(Ci-C6 alkyl)2), 0-PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl m= 0, l, or 2 n= 1 or 2; p=2 to 6 q= 4 or 5
In one of the embodiments of the invention, derivatives of 1,3-diphenylpropane are compounds of formula (IA)
Figure imgf000004_0001
(IA) wherein R, m, X 1 , X2 , X 3 , Y have the same meanings as defined for general formula (I).
In one of the embodiments of the invention, derivatives of 1,3-diphenylpropane are compounds of formula (IB)
Figure imgf000005_0001
(IB) wherein R, m, X 1 , X2 , X 3 , Y have the same meanings as defined for general formula (I).
In one of the embodiments of the invention, derivatives of 1,3-diphenylpropane are compounds of formula (IC)
Figure imgf000005_0002
(IC)
wherein R, m, X 1 , X2 , X 3 , Y have the same meanings as defined for general formula (I).
In one of the embodiments of the invention, derivatives of 1,3-diphenylpropane are compounds of formula (ID)
Figure imgf000005_0003
wherein R, m, X 1 , X2 , X 3 , Y have the same meanings as defined for general formula (I).
In one of the embodiments of the invention, derivatives of 1,3-diphenylpropane are compounds of formula (IIA)
Figure imgf000005_0004
(IIA) wherein A, B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I). In another embodiment of the invention, derivatives of 1,3-diphenylpropane can be presented by formula (IIB)
Figure imgf000006_0001
(IIB) wherein A,B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
In another embodiment of the invention, derivatives of 1,3-diphenylpropane can presented by formula (IIC)
Figure imgf000006_0002
(IIC) wherein A,B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
In still another embodiment of the invention, derivatives of 1,3-diphenylpropane are compounds of formula (IID)
Figure imgf000006_0003
(IID) wherein A,B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
In subsequent embodiments of the invention, derivatives of 1,3-diphenylpropane are compounds of formulas IIA1 - IIA4; IIB 1 - IIB4; IIC1 - IIC4; IID1 - IID4, wherein R, m,
Figure imgf000006_0004
have the same meanings as defined for general formula (I).
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
Figure imgf000007_0004
Figure imgf000007_0005
IICl IIC2
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
IID3 IID4
In particularly preferred embodiment of the invention derivative of 1,3-diphenylpropane is compound of formula (III)
Figure imgf000008_0004
(III) wherein A, B, R, Y have the same meanings as defined for general formula (I), X is H, halogen atom, OH, -0-Ci-C6alkyl, -0-CO-Ci-C6 alkyl, -0-Ci-C6alkyl(N(Ci-C6alkyl)2), O- PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl.
In another, particularly preferred embodiment of the invention derivative of 1,3- diphenylpropane is compound of formula (IV)
Figure imgf000009_0001
wherein A, B, R have the same meanings as defined for general fomiula (I), X is H, halogen atom, OH, -0-Ci-C6alkyl, -0-CO-Ci-C6 alkyl, -0-Ci-C6alkyl(N(Ci-C6alkyl)2), 0-PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl.
In one of the embodiment of the invention derivatives of 1,3-diphenylpropanes can be presented by formulas VA-VD, VIA-VID, VIIA-VIID, VIIIA-VIIID:
Figure imgf000009_0002
Figure imgf000010_0001
(VIIIC) wherein R and m have the same meanings as defined for general formula (I), X is H, halogen atom, OH, -0-Ci-C6alkyl, -0-CO-Ci-C6 alkyl, -0-Ci-C6alkyl(N(Ci-C6alkyl)2), O- PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl.
A particular group of the defined above compounds of formulas IIA1-IIA4, IIB 1-IIB4, IIC1- IIC4, IID1-IID4 and VA-VD, VIA-VID, VIIA-VIID, VIIIA-VIIID are compounds wherein m = 1, that means compounds with sulfoxide group -SO.
Another particular group of the defined above compounds of formulas IIA1-IIA4, IIB 1- IIB4, IIC1-IIC4, IID1-IID4 and VA-VD, VIA-VID, VIIA-VIID, VIIIA-VIIID are compounds wherein m = 2, that means compounds with sulfone group -S02.
Preferably, in the above compounds R is Ci-C4-alkyl group, particularly ethyl and propyl group.
Preferably, system of substituents X 1 , X2 , X 3 in the general formula (I) is as demonstrated on the Scheme below:
Figure imgf000010_0002
Derivatives of 1,3-diphenylpropane with the above systems of substituents demonstrated the highest cytotoxic activity. The term„Ci-C4-alkyl" relates to acyclic, saturated hydrocarbon group, with the indicated number of the carbon atoms that can be either a straight-chain or branched chain. Specific examples of groups included in the definition are methyl, ethyl, n-propyl, iso-propyl, n- butyl, tert-butyl, and sec-butyl groups.
The term "halogen" relates to a substituent selected from CI, F, and Br.
Compounds of general formula (I), having -0-PO(OH)2 group, may form salts with bases. The salts also constitute a subject of the invention. Particularly, the invention includes sodium, potassium and lithium salts of compounds of general formula (I).
Compounds of general formula (I), having an amino group or nitrogen heterocyclic group, may form addition salts with acids. The salts also constitute a subject of the invention.
Salts with acids may be pharmaceutically acceptable salts, especially in case they are intended to be used as component of pharmaceutical composition. The invention encompasses also salts with other than pharmaceutically acceptable acids that may be applied for example, as intermediate products in purification of compounds according to the invention.
Addition salts with acids my be formed with inorganic (mineral) acids or with organic acids. As examples of the acids, the hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, succinic, maleic, formic, acetic, glutaminic, asparaginic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethane sulfonic, naphtalenesulfonic such as 2-naphtalenesulfonic, or hexanoic acid can be listed.
Addition salt with acid may be produced by reaction of compound of general formula (I) with a suitable inorganic or organic acid, ewentually in a suitable solvent, such as an organic solvent, usually the formed salt is isolated by crystallization and filtration. For example, free bases of compounds can be transformed into related hydrochlorides by reaction of solution of the compounds, for example in methanol, with a suitable amount of hydrochloric acid or its solution in methanol, ethanol, or diethyl ether, and evaporation of the solvents. Also for example, free bases of compounds can be tansformed into related methanesufonates by addition of a suitable amount of methanesulfonic acid in methanol, ethanol or diethyl ether sulution to a solution of the compound, and subsequent evaporation of solvents or precipitation of the product. Pharmacological properties of the compounds according to the invention depend to much extend on possibility of their transformation into pro-drugs. Compounds of general formula (I) may form pharmaceutically acceptable esters and amides that can be used as pro-drugs. The simplest effect that can be achieved in result is water solubility. Derivatives substituted with hydroxyl group can be transformed into esters with phosphoric acid (compound AMG- 414), and compounds with amino group into amides of amino acids (compounds AMG-415, AMG-421). Compounds according to the invention can form in case of phenol group carbamates, and in case of an amino group derivatives with other amino acids.
The used here term "pro-drug" relates to a compound that is transformed in vivo into the parent drug, in result of particular physiological processes (for example the parent drug is formed under influence of enzymes or physiological pH).
Pro-drugs are needed, as under some circumstances, they can be applied easier than the parent drug. Pro-drug can have better than the parent drug solubility in pharmaceutical compositions, for example the pro-drug may have better water solubility, what facilitate an intravenous apllication of the drug. Pro-drug may have a better bioavailability in per-os application. After application, the pro-drug is enzymatically or chemicaly cleaved, to give the parent drug in blood or other tissues.
Exemplary pro-drugs of compounds according to the invention, include compounds wherein a hydrogen atom of amine or hydroxy group of the parent drug is replaced by a moiety such as (Ci-C6)alkanoiloxymethyl, l-((Ci-C6)alkanoiloxy)ethyl, l-methyl-l-((Ci- C6)alkanoiloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(Ci-
C6)alkoxycarbonyloaminomethyl, arylacyl and a-aminoacyl or a-aminoacyl-a-aminoacyl, wherein the above a-aminoacyl groups are independently selected from any natural, existing in proteins L-amino acids, -P(0)(OH)2, -P(0)(0(Ci-C6)alkyl)2 or glycoside (a radical formed by elimination of hydroxy group from a hemiacetal form of carbohydrate).
The invention relates also to pharmaceutical compositions containing compounds described by the formula (I), and pharmaceutically acceptable excipient, such like vehicle.
The term "pharmaceutically acceptable vehicle" relates to any vehicle used in preparation of a desired pharmaceutical dosage form. The pharmaceutically acceptable vehicle can include one or more solvents, diluents or other liquid disperging agents, additives used to prepare dispersion or suspension, detergents, isotonic agants, binders, emulgants, preservatives, lubricants and others. Remington's Pharmaceutical Sciences, XV-th Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, III- rd Ediition, A. H. Kibbe ed. (American Pharmaceutical Assoc. 2000) disclose various vehicles used in pharmaceutical compositions and known procedures for their preparation.
The invention relates also to compounds described by the above formulas for use as medicaments.
Subsequent invention relates to compounds described by the above formulas for use in treatment of cancer.
Reduction of the double bond in chalcone derivatives containing fused oxathiole, oxathiin, dioxole or dioxane ring results in compounds according to the invention that still display very strong cytotoxic activity. At the same time, due to the reduction of the double bond, the compounds according to the invention will not react nonenzymatically with cellular nucleophiles, and subsequently will cause lesser amount of adverse side effects. Chalcones may react in vivo with thiols, e.g. GSH, to give potentially severe biological consequences. The enone group of chalcones can conjugate with thiols by the Michael addition. The reactions can lead to many undesired side effects. Particularly, thiols are involved in regulation of redox equilibrium of cell, and its destabilizations may results in destabilization of synthesis of DNA, affects activation of enzymes, selectivity of genes expression, and regulation of cell cycle (P. Perjesi et al (Monatsh Chem (2012) 143: 1107-1114). Elimination of the double bond from the chalcone molecule resulted in elimination of possibility of reaction with the protein derived thiol groups, and subsequently in elimination of eventuall undesired side effects.
The presented solution is contrary to believe that cytotoxic activity of chalcones depends on their ability to react with thiols that depends on the presence of the double bond (Z. Rozmer et al., Toxicology in Vitro 2006, 20, 1354-1362).
The reduced derivatives of 1,3-diphenylpropane will display much less of side effects than their analogs with enone moiety. The effect, besides of cytotoxic activity is characteristic for compounds according to the said invention.
The compounds according to the invention are produced using methods generally known in the state of the art, according to the Schemes below. 
Figure imgf000014_0001

Figure imgf000015_0001
Compounds prepared as demonstrated on the above Schemes can be transformed further, as demonstrated in Examples. Especially, the degree of oxidation of sulfur atom in compounds of general formula (I) can be modified using the known in the state of the art methods of oxidation of sulfur compounds. Compounds of general formula (I) can be transformed into their pro-drugs of eter, carbamate, ester or amide character, using methods known in the state of the art, as demonstrated in Examples.
Compound of formula (IIA) is prepared by reaction of chalcone,
Figure imgf000016_0001
wherein A, B, R, X have the same meanings as defined for a related compound (IIA), with hydrogen, in a presence of a catalyst.
The reaction is performed by stirring a mixture, for example of solution of a suitable chalcone in solvent like ethyl acetate, in the presence of a catalyst such as palladium on charcoal, under atmosphere of hydrogen, at room temperature, until chromatographic analysis demonstrate that the substrate have reacted completely. The product is isolated using generaly known methods.
Derivatives of 1,3-diphenylpropane of formulas VA to VD and VIIIA to VIIID, wherein R and m have the same meanings as defined above for formula (I), and X is -0-PO(OH)2, and their salts with alkali metals, may by obtained from related compounds of general formula (I), wherein X is OH, by reaction with phosphorous oxychloride P(0)C13 or by an alternative methods described in the state of the art for similar derivatives of phenol.
The invention is explained below in Examples.
Example 1. Preparation of compounds of formula (I) wherein Y = O
Figure imgf000016_0002
A mixture of a suitable starting compound, obtained according to a method known from WO 11/009826 A2, and palladium on charcoal as catalyst (in case of substrates with non- oxidized sulfur atom, largel than usuall amount of the catalyst has to be used), in ethyl acetate is hydrogenated with gaseous hydrogen, at room temperature. When a control demonstrate that the substrate reacted completely, the catalyst is filtered off, and the filtrate is evaporated to dryness. The residue is crystallized from a suitable solvent or purified on silica gel chromatographic column, to give the product.
Figure imgf000017_0001
Using the described above procedure of synthesis of compounds of general formula (I), wherein Y = O, 3-(3-hydroxy-4-methoxyphenyl)-l-(7-propoxy-2,3- dihydrobenzo[ ][l,4]oxathiin-6-yl)propen-l-one (193 mg, 0,5 mmol), and 10 % palladium on charcoal (250 mg) in ethyl acetate were stirred at room temperature, under hydrogen, for 50 hours. The catalyst was filtered off, and the filtrate was evaporated to give a colorless oil. The crude product was purified on silica gel chromatographic column in methylene chloride, and next crystallized from methanol to give 3-(3-hydroxy-4-methoxyphenyl)-l-(7-propoxy- 2,3-dihydrobenzo[ ][l,4]oxathiin-6-yl)propan-l-one as a colorless solid, yield 104 mg (53 %), mp. (°C): 116 - 118. NMR (500 MHz, DMSO-d6): δ 8,79 (s, 1 H, OH), 7,32 (s, 1 H, H- 5), 6,79 (d, 1 H, J = 8,2 Hz, H-5'), 6,62 (d, 1 H, J = 2,0 Hz, H-2'), 6,60 (s, 1 H, H-8), 6,56 (dd, 1 H, Ji = 8,2 Hz, J2 = 2,0 Hz, H-6'), 4,43 (m, 2 H, H-2), 3,98 (t, 2 H, J = 6,3 Hz, OCH2), 3,72 (s, 3 H, OCH3), 3,17 (m, 4 H, H-3 + Η-β) 2,74 (t, 2 H, J = 7,6 Hz, H-a), 1,73 (m, 2 H, CH2), 0,96 (t, 3 H, J = 7,4 Hz, CH3). IR (KBr, cm"1): 3405, 1657, 1596, 1513, 1269, 1193, 1173, 1086.
Using the described above procedure of synthesis of compounds of general formula (I), wherein Y = O, and demonstrated for compound AMG-391, the following compounds were obtained:
AMG-407
Figure imgf000017_0002
3 -(3 -amino-4-methoxyphenyl) - 1 -(7 -propoxy-2,3 -dihydrobenzo [b] [1,4] oxathiin-6-yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 7,29 (s, 1 H, H-5), 6,64 (d, 1 H, J = 8,1 Hz, H-5'), 6,57 (s, 1 H, H-8), 6,45 (d, 1 H, J = 1,9 Hz, H-2'), 6,31 (dd, 1 H, = 8,1 Hz, J2 = 1,9 Hz, H- 6'), 4,57 (s, 2 H, NH2), 4,40 (m, 2 H, H-2), 3,96 (t, 2 H, J = 6,3 Hz, OCH2), 3,69 (s, 3 H, OCH3), 3,13 (m, 4 H, H-3 + CH2CO), 2,67 (t, 2 H, J = 7,6 Hz, CH2Ph), 1,71 (m, 2 H, CH2), 0,94 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000018_0001
3-(3-fluoro-4-methoxyphenyl)-l-(7-propoxy-2,3-di ydrobenzo[&][l,4]oxathiin-6-yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 7,33 (s, 1 H, H-5), 7,02 - 7,08 (m, 2 H, H-2', H-6'), 6,96 (d, 1 H, J = 8,3 Hz, H-5'), 6,59 (s, 1 H, H-8), 4,43 (m, 2 H, H-2), 3,97 (t, 2 H, J = 6,3 Hz, OCH2), 3,80 (s, 3 H, OCH3), 3,22 (t, 2 H, J = 7,5 Hz, COCH2), 3,17 (m, 2 H, H-3), 2,82 (t, 2 H, J = 7,5 Hz, CH2Ph), 1,72 (m, 2 H, CH2), 0,94 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000018_0002
3 -(3 -hydroxy-4-methoxyphenyl) - 1 -(4,4-dioxo-7-propoxy-2,3 -dihydrobenzo [b] [ 1 ,4] oxathiin- 6-yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 8,79 (s, 1 H, OH), 7,93 (s, 1 H, H-5), 6,79 (m, 2 H, H-6', H-8), 6,63 (s, 1 H, H-2'), 6,56 (d, 1 H, J = 8,2 Hz, H-5'), 4,84 (m, 2 H, H-3), 4,10 (t, 2 H, J = 6,3 Hz, OCH2), 3,85 (m, 2 H, H-2), 3,72 (s, 3 H, OCH3), 3,21 (t, 2 H, J = 7,4 Hz, COCH2), 2,76 (t, 2 H, J = 7,4 Hz, CH2Ar), 1,76 (m, 2 H, CH2), 0,96 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000018_0003
3-(3-amino-4-methoxyphenyl)-l-(4,4-dioxo-7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6- yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 7,90 (s, 1 H, H-5), 6,76 (s, 1 H, H-8), 6,64 (d, 1 H, J = 8,1 Hz, H-5'), 6,46 (d, 1 H, J = 1,4 Hz, H-2'), 6,32 (dd, 1 H, = 8,1 Hz, J2 = 1,4 Hz, H-6'), 4,82 (m, 2 H, H-3), 4,58 (s, 2 H, NH2), 4,08 (t, 2 H, J = 6,3 Hz, OCH2), 3,83 (m, 2 H, H-2), 3,69 (s, 3 H, OCH3), 3,16 (t, 2 H, J = 7,6 Hz, CH2CO), 2,70 (t, 2 H, J = 7,6 Hz, CH2Ph), 1,75 (m, 2 H, CH2), 0,95 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000019_0001
3-(3-amino-4-methoxyphenyl)-l-(6-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-7-yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 6,98 (s, IH, H-8), 6,84 (s, IH, H-5), 6,64 (d, IH, J = 8,1 Hz, H-5'), 6,45 (d, IH, J = 2.1 Hz, H-2'), 6,32 (dd, IH, = 8,1 Hz, J2 = 2.1 Hz, H-6'), 4,58 (s, 2H, NH2), 4,28 (m, 2H, H-2), 3,95 (t, 2H, J = 6,4 Hz, OCH2), 3,69 (s, 3H, OCH3), 3,20 (m, 2H, H-3), 3,14 (t, 2H, J = 7,7 Hz, COCH2), 2,68 (t, 2H, J = 7,7 Hz, CH2Ph), 1,70 (m, 2H, CH2), 0,93 (t, 3H, J = 7,4 Hz, CH3).
Figure imgf000019_0002
3-(3-amino-4-methoxyphenyl)-l-(4,4-dioxido-6-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin- 7-yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 7,30 (s, IH, H-5), 7,06 (s, IH, H-8), 6,64 (d, IH, J = 8,0 Hz, H-5'), 6,45 (d, IH, J = 2.0 Hz, H-2'), 6,32 (dd, IH, Ji = 8,0 Hz, J2 = 2.0 Hz, H-6'), 4,71 (m, 2H, H-2), 4,59 (s, 2H, NH2), 4,03 (t, 2H, J = 6,3 Hz, OCH2), 3,85 (m, 2H, H-3), 3,69 (s, 3H, OCH3), 3,13 (t, 2H, J = 7,5 Hz, COCH2), 2,69 (t, 2H, J = 7,7 Hz, CH2Ph), 1,70 (m, 2H, CH2), 0,93 (t, 3H, J = 7,3 Hz, CH3).
Figure imgf000020_0001
3-(3-hydroxy-4-methoxyphenyl)-l-(5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan- 1-one.
NMR (500 MHz, DMSO-d6): δ 8,78 (s, 1 H, OH), 7,23 (s, 1 H, H-7), 7,01 (s, 1 H, H-4), 6,79 (d, 1 H, J = 8,2 Hz, H-5), 6,62 (d, 1 H, J = 1,7 Hz, H-2'), 6,56 (dd, Ji = 8,2 Hz, J2 = 1,7 Hz), 5,77 (s, 2 H, H-2), 4,00 (7, 2 H, J = 6,4 Hz, OCH2), 3,72 (s, 3 H, OCH3), 3,18 (t, 2 H, J = 7,5 Hz, COCH2), 2,74 (t, 2 H, J = 7,5 Hz, CH2Ph), 1,73 (m, 2 H, CH2), 0,95 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000020_0002
3-(3-fluoro-4-methoxyphenyl)-l-(5-methoxybenzo[<i][l,3]oxathiol-6-yl)propan- 1-one. (500 MHz, DMSO-d6): δ 7,26 (s, 1 H, H-7), 7,04 - 7,11 (m, 2 H, H-2', H-6'), 7,04 (s, 1 H, H-4), 6,98 (d, 1 H, J = 8,3 Hz, H-5'), 5,78 (s, 2 H, H-2), 3,83 (s, 3 H, OCH3), 3,80 (s, 3 H, OCH3), 3,17 (t, 2 H, J = 7,4 Hz, COCH2), 2,81 (t, 2 H, J = 7,4 Hz, CH2Ph).
Figure imgf000020_0003
3-(3-hydroxy-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan- 1-one. NMR (500 MHz, DMSO-d6): δ 8,81 (s, 1 H. OH), 7,63 (s, 1 H, H-4), 7,28 (s, 1 H, H- 7), 6,79 (d, 1 H, J = 8,2 Hz, H-5'), 6,63 (d, 1 H, J = 1,9 Hz, H-2'), 6,56 (dd, 1 H, Ji = 8,2 Hz, h = 1,9 Hz, H-6'), 5,42 (s, 2 H, H-2), 4,08 (t, 2 H, J = 6,3 Hz, OCH2), 3,72 (s, 3 H, OCH3), 3,18 (t, 2 H, J = 7,5 Hz, COCH2), 2,77 (t, 2 H, J = 7,5 Hz, CH2Ph), 1,71 (m, 2 H, CH2), 0,94 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000021_0001
3-(3-amino-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- one. NMR (500 MHz, DMSO-d6): δ 7,63 (s, 1 H, H-4), 7,28 (s, 1 H, H-7), 6,67 (d, 1 H, J = 8,1 Hz, H-5'X 6,47 (d, 1 H, J = 1,5 Hz, H-2'), 6,34 (dd, 1 H, = 8,1 Hz, J2 = 1,5 Hz, H-6'), 5,42 (s, 2 H, H-2), 4,61 (s, 2 H, NH2), 4,09 (t, 2 H, J = 6,3 Hz, OCH2), 3,71 (s, 3 H, OCH3), 3,15 (t, 2 H, J = 7,5 Hz, COCH2), 2,72 (t, 2 H, J = 7,5 Hz, CH2Ph), 1,72 (m, 2 H, CH2), 0,95 (t, 3 H, J = 7,4 Hz, CH3).
Figure imgf000021_0002
3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- one. NMR (500 MHz, DMSO-d6): δ 7,61 (s, 1 H, H-4), 7,29 (s, 1 H, H-7), 7,06 (dd, 1 H, Ji = 13,2 Hz, h= 1,9 Hz, H-2'), 7,02 (d, 1 H, J = 8,6 Hz, H-5'), 6,96 (d, 1 H, J = 8,6 Hz, H-6'), 5,40 (s, 2 H, H-2), 4,05 (t, 2 H, J = 6,3 Hz, OCH2), 3,78 (s, 3 H, OCH3), 3,22 (t, 2 H, J = 7,4 Hz, COCH2), 2,83 (t, 2 H, J = 7,4 Hz, CH2Ph), 1,67 (m, 2 H, CH2), 0,90 (t, 3 H, J = 7,4 Hz, CH3).
Example 2. Preparation of derivatives of compounds of general formula (I), wherein Y = O (carbonyl) and one of the substituents X = NHCOCHRiNH2 (synthesis of pro-drugs with amino acids)
Figure imgf000021_0003
A suitable starting compound, prepared according to the procedure described above, is condensed with a suitable derivative of amino acid with protected amino group, using generally known procedures, for example condensation in a presence of dicyclohexylcarbodiimide in methylene chloride solution. The obtained product is purified using column chromatography on silica gel column or is crystallized from a suitable solvent. The obtained conjugate is deprotected using generally known methods, for example, deprotection of t-butylcarbamoyl group is carried out with a solution of trifluoroaeetie acid in methylene chloride. The obtained product is purified using chromatography on silica gel column or by crystallization from a suitable solvent. Optionally, the obtained product is treated with a protic acid to give a suitable salt.
Figure imgf000022_0001
Using the described above procedure for preparation of compounds of formula (I), wherein Y = O (carbonyl) and one of the substituents X = NHCOCHRiNH2, a solution of 3-(3- amino-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l-one (202 mg, 0,5 mmol), Boc-L-leucine (139 mg, 0,6 mmole) and Ν,Ν'- dicyclohexylcarbodiimide (165 mg, 0,8 mmole) in anhydrous methylene chloride (5 ml) was stirred at room temperature for 18 hours. The precipitated solid was filtered off, the filtrate was evaporated, and the residue was purified on silica gel chromatographic column in methylene chloride - ethyl acetate 20 : 1 solution. The obtained product was crystallized from ethanol, to give (S)-tert-butyl l-(2-methoxy-5-(3-oxo-3-(3,3-dioxo-5- propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)phenylamino)-4-methyl-l-oxopentan-2-yl carbamate as a colorless solid, yield 200 mg (65 %). NMR (500 MHz, DMSO-d6): δ 8,89 (s, 1 H, NH), 7,95 (s, 1 H, H-2'), 7,60 (s, 1 H, H-4), 7,37 (d, 1 H, J = 7,6 Hz, NH), 7,28 (s, 1 H, H-7), 6,93 (d, 1 H, J = 8,4 Hz, H-5'), 6,88 (d, 1 H, J = 8,4 Hz, H-6'), 5,40 (s, 2 H, H-2), 4,05 (m, 3 H, OCH2 + CH), 3,79 (s, 3 H, OCH3), 3,18 (t, 2 H, J = 7,4 Hz, CH2CO), 2,81 (t, 2 H, J = 7,4 Hz, CH2Ph), 1,68 (m, 3 H, CH2 + CH), 1,52 (m, 2 H, CH2), 1,40 (s, 9 H, 3 x CH3), 0,89 (m, 9 H, 3 x CH3). IR (KBr, cm"1): 3422, 2961, 2930, 1686, 1538, 1463, 1418, 1325, 1255, 1171, 1146, 1014. NH2
AMG-415 CH2CH(CH3)2
Trifluoroacetic acid (2 ml) was added to a solution of (S)-tert-butyl l-(2-methoxy-5-(3-oxo- 3-(3,3-dioxo-5-propoxybenzo[<i] [l,3]oxathiol-6-yl)propyl)phenylamino)-4-methyl- l- oxopentan-2-yl carbamate (500 mg, 0,81 mmol) in anhydrous methylene chloride (10 ml), and the mixture was stirred at room temperature for 2 hours. The obtained solution was poured into a stirred solution of sodium bicarbonate in ice cooled water, and the resulted mixture was extracted with ethyl acetate (100 ml). The organic layer was washed with sodium bicarbonate solution (1 x 10 ml), brine (1 x 50 ml), and dried (Na2S04). The solution was evaporated to dryness, and the residue was crystallized from ethanol to give (S)-2- amino-N-(2-methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[<i] [l,3]oxathiol-6- yl)propyl)phenyl)-4-methylpentanamide as a creem solid, yield (71%). NMR (500 MHz, DMSO-d6): δ 10,13 (bs, 1 H, NH), 8,14 (s, 1 H, H-2'), 7,60 (s, 1 H, H-4), 7,27 (s, 1 H, H-7), 6,92 (d, 1 H, J = 8,4 Hz, H-5'), 6,85 (d, 1 H, J = 8,4 Hz, H-6'), 5,40 (s, 2 H, H-2), 4,05 (t, 2 H, J = 6,3 Hz, OCH2), 3,80 (s, 3 H, OCH3), 3,33 (bs, under H20, CH), 3,18 (t, 2 H, J = 7,4 Hz, CH2CO), 2,81 (t, 2 H, J = 7,4 Hz, CH2Ph), 1,78 (m, 1 H, CH), 1,69 (m, 2 H, CH2), 1,56 (m, 1 H, CH), 1,33 (m, 1 H, CH), 0,89 (m, 9 H, 3 x CH3). JR (KBr, cm"1): 3405, 3330, 2954, 1679, 1535, 1463, 1417, 1324, 1147, 1017.
Using the described above procedure for preparation of compounds of general formula (I), wherein Y = O and one of the substituents X = NHCOCHRiNH2, and demonstrated for compounds AMG-419, and AMG-415, the following compounds were obtained:
Figure imgf000023_0001
(S )-2-amino-N-(2-methoxy-5 -(3 -oxo-3 -(7-propoxy-2,3 -dihydrobenzo [b] [ 1 ,4] oxathiin-6- yl)propyl)phenyl)-4-methylpentanamide. NMR (500 MHz, D20) (spectrum for hydrochloride): δ 7,33 (s, 1 H, H-2'), 7,03 (s, 1 H, H-8), 6,71 (bs, 2 H, H-5', H-6'), 6, 11 (s, 1 H, H-5), 4,17 (s, 2 H, H-2), 4,09 (m, 1 H, LeuCH), 3,63 (s, 3 H, OCH3), 3,53 (s, 2 H, OCH3), 2,91 (s, 2 H, CH2CO), 2,83 (s, 2 H, H-3), 2,59 (s, 2 H, CH2Ph), 1,64 (m, 2 H, propylCH2), 1,54 (m, 1 H, LeuCH), 1,45 (m, 2 H, LeuCH2), 0,81 (d, 3 H, J = 6,3 Hz, CH3), 0,79 (d, 3 H, J = 6,3 Hz, CH3), 0,69 (t, 3 H, J = 7,0 Hz, CH3).
AMG-488
Figure imgf000024_0001
Using compound AMG-487 as a substrate, (S)-2-amino-N-(5-(3-(3,3-dioxido-5- propoxybenzo[<i] [ 1 ,3]oxathiol-6-yl)propyl)-2-methoxyphenyl)-4-methylpentanamide was obtained. NMR (500 MHz, DMSO-d6): δ 10,16 (bs, IH, NH), 8,15 (d, IH, J = 2,0 Hz, H-2'), 7,28 (s, IH, H-4), 7,13 (s, IH, H-7), 6,92 (d, IH, J = 8,3 Hz, H-5'), 6,81 (dd, IH, = 8,2 Hz, h = 2,2 Hz, H-6'X 5,30 (s, 2H, H-2), 3,93 (t, 2H, J = 6,2 Hz, OCH2), 3,80 (s, 3H, OCH3), 3,27 (m, IH, CH), 2,60 (m, 2H, CH2), 2,51 (t, 2H, J = 7,5 Hz, CH2), 2,19 (bs, 2H, NH2), 1,76 (m, 2H, CH2), 1,67 (m, 2H, CH2), 1,54 (m, IH, CH), 1,30 (m, IH, CH), 0,84 - 0,94 (m, 9H, 3 x CH3).
AMG-484
Figure imgf000024_0002
Using compound AMG-483 as a substrate, (S)-2-amino-N-(5-(3-(4,4-dioxido-6-propoxy- 2,3-dihydrobenzo[ ] [ 1 ,4]oxathiin-7-yl)propyl)-2-methoxyphenyl)-4-methylpentanamide was obtained. NMR (500 MHz, DMSO-d6) (spectrum for hydrochloride): δ 9,80 (s, IH,
NH), 8,32 (s, 3H, NH3 +), 7,67 (s, IH, H-2'), 7,04(s, IH, H-5), 6,98 (d, IH, J = 8,3 Hz, H-5'), 6,94 (t, IH, J = 8,4 Hz, H-6'), 6,88 (s, IH, H-8), 4,67 (m, 2H, H-2), 4,15 (m, IH, CH), 3,90 (t, 2H, J = 6,2 Hz, OCH2), 3,80, s, 3H, OCH3), 3,75 (m, 2H, H-3), 2,51, m, 4H, 2 x CH2), 1,76 (m, 2H, CH2), 1,65 (m, 5 H, 2 x CH2, CH), 0,91 (m, 9H, 3 x CH3). AMG-486
Figure imgf000025_0001
Using compound AMG-485 as a substrate, (S)-2-amino-N-(2-methoxy-5-(3-(6-propoxy-2,3- dihydrobenzo[ ] [ 1 ,4]oxathiin-7-yl)propyl)phenyl)-4-methylpentanamide was obtained. NMR (500 MHz, DMSO-d6) (spectrum for hydrochloride): δ 9,81 (s, 1H, NH), 8,35 (s, 3H, NH3 +), 7,66 (s, 1H, H-2'), 6,95 (m, 2H, H-5', H-6"), 6,58 (s, 1H, H-8), 6,55 (s, 1H, H-5), 4,24 (m, 1H, H-2), 4,15 (m, 1H, CH), 3,79 (s, 3H, OCH3), 3.78 (t, 2H, J = 6,4 Hz, OCH2), 3,12 (m, 2H, H-3), 2.5 (m, under DMSO, CH2), 2.44 (t, 2H, J = 7,6 Hz, CH2), 1,72 (m, 3H, CH2, CH), 1,63 (m, 3H, CH2, CH), 0,91 (m, 9H, 3x CH3).
Example 3. Preparation of compounds of general furmula (I), wherein Y
and one of the substituents X = OCOCH3 (synthesis of acyl pro-drugs).
Figure imgf000025_0002
2- methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)phenyl acetate
3- (3-Hydroxy-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propan-l-one (404 mg, 1 mmol) was suspended in acetyl anhydride (4 ml), catalytic amount of concentrated sulfuric acid was added, and the mixture was stirred at room temperature for 30 minutes. Water and ice were added to the mixture, and after 1 hour the precipitated solid was filtered off, and crystallized from methanol to give 2-methoxy-5-(3- oxo-3-(3,3-dioxo-5-propoxybenzo[d][l,3]oxathiol-6-yl)propyl)phenyl acetate (360 mg, 80
%), m.p. 98-99 °C. NMR (500 MHz, DMSO-d6): δ 7,63 (s, 1 H, H-4), 7,30 (s, 1 H, H-7), 7,08 (dd, 1 H, Ji = 8,4 Hz, J2 = 1,9 Hz, H-6'), 7,02 (d, 1 H, J = 8,4 Hz, H-5'), 6,94 (d, 1 H, J = 1,9 Hz, H-2'), 5,42 (s, 2 H, H-2), 4,08 (t, 2 H, J = 6,4 Hz, OCH2), 3,73 (s, 3 H, OCH3), 3,24 (t, 2 H, J = 7,4 Hz, COCH2), 2,85 (t, 2 H, J = 7,4 Hz, CH2Ph), 2,24 (s, 3 H, COCH3), 1,70 (m, 2 H, CH2), 0,93 (t, 3 H, J = 7,5 Hz, CH3).
Example 4. Preparation of derivatives of compounds of general formula (I), wherein Y = (carbonyl) and one of the substituents X = OP03Na2 (synthesis of phosphate pro-drugs).
Figure imgf000026_0001
Figure imgf000026_0002
Sodium 2-methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[d][l,3]oxathiol-6- yl)propyl)phenyl phosphate
3-(3-Hydroxy-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propan-l-one (916 mg, 2.25 mmol) was added to a stirred solution of phosphorous oxychloride (2,3 ml, 25 mmol) and trimethylamine (7 ml, 50 mmol) in anhydrous methylene chloride (90 ml) at room temperature, and the mixture was stirred at room temperature for 40 minutes. The mixture was cooled in ice, IN solution of sodium hydroxide in water (230 ml) was added, and the whole was stirred at room temperature for 20 hours. The obtained layers were separated, the aqueous one was washed with methylene chloride, acidified with IN hydrochloric acid, and extracted twice with ethyl acetate (200 ml). The organic layer was washed with brine, dried with anhydrous sodium sulfate, and evaporated. Methanol (7 ml), followed by IN solution of sodium hydroxide in methanol were added to the residue, and the obtained suspension was diluted with ethanol (20 ml). The solid was filtered off and washed with ethanol to give a yellow solid of sodium 2-methoxy-5-(3-oxo-3-(3,3-dioxo-5- propoxybenzo[d][l,3]oxathiol-6-yl)propyl)phenyl phosphate (700 mg 95 %), m.p. 165 - 168
°C. NMR (500 MHz, D20): δ 7,30 (s, 1 H, H-4), 7,16 (s, 1 H, H-2'), 7,07 (s, 1 H, H-7), 6,75 (d, 1 H, J = 8,3 Hz, H-5'), 6,63 (d, 1 H, J = 8,3 Hz, H-6'), 5,15 (s, 2 H, H-2), 3,89 (t, 2 H, J = 6,3 Hz, OCH2), 3,67 (s, 3 H, OCH3), 3,21 (t, 2 H, J = 7,2 Hz, CH2CO), 2,77 (t, 2 H, J = 7,2 Hz, CH2Ph), 1,61 (m, 2 H, CH2), 0,81 (t, 3 H, J = 7,4 Hz, CH3). IR (KBr, cm"1): 3428, 1685, 1515, 1462, 1416, 1305, 1157, 988.
Example 5. Preparation of compounds of general formula (I), wherein Y
Figure imgf000027_0001
Suitable starting compound, prepared as described above in Examples 1 - 4, is reduced using generally known methods, for example reduction with zinc in acetic acid solution, or reduction with sodium borohydride or its derivative in a solution in protic solvent. The obtained product is purified using silica gel column chromatography, or by crystallization from a suitable solvent.
Figure imgf000027_0002
3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- ol
Using the described above procedure for preparation of compounds of general formula (I), wherein Y = OH, a mixture of 3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5- propoxybenzo[d][l,3]oxathiol-6-yl)propan-l-one (110 mg, 0,27 mmol) and zinc dust (150 mg, 2,3 mmol) in acetic acid (3 ml) and water (1 ml) was stirred at room temperature for 19 hours, and next extracted with methylene chloride (50 ml). The organic solution was washed with water (3 x 20 ml), dried (Na2S04), and evaporated to dryness. The residue was crystallized from methanol to give 3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5- propoxybenzo[d][l,3]oxathiol-6-yl)propan-l-ol as a colorless solid, (60 mg, 54 %). M.p.
(°C): 139 - 140. NMR (500 MHz, DMSO-d6): δ 7,29 (s, 1 H, H-4 or H-7), 7,27 (s, 1 H, H-4 or H-7), 6,92 - 7,05 (m, 2 H, H-2', H-6'), 6,93 (d, 1 H, J = 8,3 Hz, H-5'), 5,42 (d, 1 H, J = 4,8 Hz, OH), 5,33 (d, 1 H, J = 10,6 Hz, H-2), 5,31 (d, 1 H, J = 10,6 Hz, H-2), 4,77 (m, 1 H, CHOH), 3,95 (m, 1 H, OCH2), 3,88 (m, 1 H, OCH2), 3,78 (s, 3 H, OCH3), 2,64 (t, 2 H, J = 7,2 Hz, CH2Ph), 1,84 (m, 1 H, CH(OH)CH2), 1,61 (m, 3 H, CH(OH)CH2 + CH2propyl), 0,85 (,t, 3 H, J = 7,4 Hz, CH3). IR (KBr, cm"1): 3569, 1521, 1463, 1313, 1277, 1143, 1068, 1027, 964.
Using the described above procedure for preparation of compounds of general formula (I), wherein Y = OH, and demonstrated for compound AMG-430, the following compounds were obtained:
Figure imgf000028_0001
5-(3-hydroxy-3-(4,4-dioxo-7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6-yl)propyl)-2- methoxyphenol. NMR (500 MHz, DMSO-d6): δ 8,75 (s, 1 H, OH), 7,71 (s, 1 H, H-5), 6,78 (d, 1 H, J = 8,2 Hz, H-5'), 6,59 (d, 1 H, J = 2,0 Hz, H-2'), 6,53 (m, 2 H, H-6' + H-8), 5,28 (d, 1 H, J = 5,2 Hz, OH), 4,73 (m, 3 H, H-a + H-3), 3,85 - 3,98 (m, 2 H, OCH2), 3,75 (m, 2
H, H-2), 3,72 (s, 3 H, OCH3), 2,56 (m, 2 H, H-c), 1,83 (m, 1 H, H-b), 1,67 (m, 2 H, CH2),
I, 60 (m, 1 H, H-b), 0,91 (t, 3 H, J = 7,3 Hz, CH3).
Figure imgf000028_0002
5-(3-hydroxy-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2-methoxyphenol. NMR (500 MHz, DMSO-d6): δ 8,75 (s, 1 H, OH), 7,32 (s, 1 H, H-4), 7,28 (s, 1 H, H-7), 6,78 (d, 1 H, J = 8,0 Hz, H-5'), 6,60 (s, 1 H, H-2'), 6,55 (d, 1 H, J = 8,0 Hz, H-6'), 5,40 (s, 1 H, OH), 5,35 (s, 2 H, H-2), 4,83 (m, 1 H, H-a), 3,96 (m, 2 H, OCH2), 3,72 (s, 3 H, OCH3), 2,56 (m, 2 H, H-c), 1,85 (m, 1 H, H-b), 1,65 (m, 3 H, H-b + CH2), 0,91 (t, 3 H, J = 7,2 Hz, CH3).
Figure imgf000029_0001
3 -(3 -hydroxy-3 -(3 ,3 -dioxo-5-propoxybenzo [d] [ 1 ,3 ] oxathiol-6-yl)propyl)-2-methoxyaniline. NMR (500 MHz, DMSO-d6): δ 7,30 (s, 1 H, H-4), 7,26 (s, 1 H, H-7), 6,63 (d, 1 H, J = 8,2 Hz, H-5'), 6,43 (d, 1 H, J = 2,0 Hz, H-2'), 6,31 (dd, 1 H, = 8,2 Hz, J2 = 2,0 Hz, H-6'), 5,36 (d, 1 H, J = 5,0 Hz, OH), 5,34 (d, 1 H, J = 10,6 Hz, H-2), 5,31 (d, 1 H, J = 10,6 Hz, H- 2), 4,83 (m, 1 H, H-a), 4,55 (s, 2 H, NH2), 3,88 - 4,00 (m, 2 H, OCH2), 3.68 (s, 3 H, OCH3), 2,40 - 2,55 (m, under DMSO, H-c), 1,82 (m, 1 H, H-b), 1,66 (m, 2 H, CH2), 1,59 (m, 1 H, H-b), 0,91 (t, 3 H, J = 7,3 Hz, CH3).
Example 6. An example of preparation of pro-drug of compound of general formula (I), wherein Y = OH, and one of the substituents X = NHCOCHRiNH2 (synthesis of pro-drug with aminoacid)
Figure imgf000029_0002
Figure imgf000029_0003
(2S)-2-amino-N-(5-(3-hydroxy-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)- 2-methoxyphenyl)-4-methylpentanamide
(S)-2-amino-N-(2-methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propyl)phenyl)-4-methylpentanamide (300 mg, 0,58 mmol), prepared as described in the Example 2, was dissolved in hot ethanol (20 ml), cooled in ice, and sodium borohydride (44 mg, 1,16 mmol) was added to the stirred solution. The mixture was stirred for 80 minutes, while the temperature raised to room temperature. Next, water was added (20 ml), the precipitated solid was filtered off, washed with water, and crystallized from ethanol to give (2S)-2-amino-N-(5-(3-hydroxy-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)- 2-methoxyphenyl)-4-methylpentanamide as a colorless solid (253 mg, 84 %). The solid was suspended in anhydrous methanol (2 ml), and solution of methanesulfonic acid (0,1 ml, 1,5 mmol) in anhydrous methanol (1 ml) was added. The obtained solution was gradually diluted with ethyl ether (40 ml). The precipitated solid was filtered off, and washed with ethyl ether to give (2S)-2-amino-N-(5-(3-hydroxy-3-(3,3-dioxo-5- propoxybenzo[<i] [ 1 ,3]oxathiol-6-yl)propyl)-2-methoxyphenyl)-4-methylpentanamide methanesulfonate as a colorless solid, yield 255 mg, 69 %. NMR (500 MHz, D20): δ 10,16 (bs, 1 H, NH), 8,15 (2 x d, 1 H, J = 2,1 Hz, H-2'), 7,29 (s, 1 H, H-4 or H-7), 7,27 (s, 1 H, H- 4 or H-7), 6,90 (d, 1 H, J = 8,2 Hz, H-5'), 6,81 (m, 1 H, H-6'), 5,42 (m, 1 H, OH), 5,34 (d, 1 H, J = 10,5 Hz, H-2), 5,31 (d, 1 H, J = 10,5 Hz, H-2), 4,81 (m, 1 H, CH), 3,95 (m, 1 H, OCH), 3,90 (m, 1 H, OCH), 3,80 (s, 3 H, OCH3), 3,28 (bd, 1 H, CH), 2,60 (m, 2 H, CH2), 2,20 (bs, 2 H, NH2), 1,85 (m, 1 H, CH), 1,78 (m, 1 H, CH), 1,5 - 1,69 (m, 4 H, CH2 + CH + CH), 1,30 (m, 1 H, CH), 0,88 (m, 9 H, 3 x CH3). IR (KBr, cm"1): 3410, 2961, 1674, 1548, 1464, 1314, 1161, 1043.
Example 7. Preparation of compounds of formula (I), wherein Y = H
Figure imgf000030_0001
An excess of triethylsilane is added dropwise to a stirred mixture of suitable chalcone and trifluoroacetic acid, and the whole is stirred at room temperature until the end of the reduction. The product is isolated using generally known methods, for example the reaction mixture is poured into a stirred solution of sodium carbonate in water, and product is filtered off or extracted with an organic solvent, for example with ethyl acetate. The crude product is purified by crystallization or using chromatographic methods.
Figure imgf000030_0002
3-(4-methoxy-3-nitrophenyl)-l-(6-propoxybenzo[^][l,4]-oxathian-7-yl)propane Using the described above procedure for preparation of compounds of general formula (I), wherein Y H, (E)-3-(4-methoxy-3-nitrophenyl)- l-(3,3-dioxo-5- propoxybenzo[d] [l,3]oxathiol-6-yl)prop-2-en-l-one (0,433 g, 1 mmol) was dissolved in trifluoroacetic acid (4 ml). The solution was cooled in ice- water bath, and triethylsilane (1 ml, 6,28 mmol) was added dropwise, with stirring. Next, the solution was stirred at room temperature for 40 minutes, and poured into a stirred solution of sodium carbonate 10 g (0,09 mola) in water (100 ml). The precipitated solid was filtered off, washed with water, and crystallized from ethyl acetate, to give 3-(4-methoxy-3-nitrophenyl)- l-(6- propoxybenzo| ] [l,4]-oxathian-7-yl)propane, m.p. 183-185°C. 1H NMR (DMSO-d6) δ 7.68 (d, IH, J = 2,0 Hz, H-2'), 7.47 (dd, IH, Ji = 8,6 Hz, J2 = 2,1 Hz, H-6'), 7.26 (m, 3H, H-4, H- 7, H-5'), 5.49 (d, IH, J = 5,0 Hz, OH), 5.34 (d, IH, J = 9,5 Hz, H-2), 5.31 (d, IH, J = 9,5 Hz, H-2), 4.76 (bs, CHOH), 3.87 (m, 5H, OCH2, OCH3), 2.72 (t, 2H, J = 7,2 Hz, CH2), 1.84-1.9 (m, IH, CH), 1.65- 1.75 (m, IH, CH), 1.5- 1.6 (m, 2H, CH2), 0.81 (t, 3 H, J=7,4 Hz, CH3). IR (cm"1): 3425, 2925, 1623, 1531, 1464, 1304, 1278, 1163.
Using the described above procedure for preparation of compounds of general formula (I), wherein Y = H, the following compounds were obtained:
Figure imgf000031_0001
3-(4-methoxy-3-nitrophenyl)- l-(5-propoxybenzo[^] [l,4]-oxathiol-6-yl)propane. M.p. 53-
56°C. 1H NMR (DMSO-d6) δ 7.67 (d, IH, J=2, l Hz, H-2'), 7.46 (dd, IH, Ji=8,7 Hz, J2=2,3 Hz, H-6'), 7.25 (d, IH, J=8,7 Hz, H-5'), 6.92 (s, IH, H-7), 6.69 (s, IH, H-4), 3.87 (s, 3H, OCH3), 3.80 (t, 2H, J=6,3 Hz, OCH2), 2.59 (t, 2H, J=7,4 Hz, CH2), 2.43-2.50 (m, 5H, 2x CH2, CH), 1.71 (m, 2H, CH2), 1.61 (m, 2H, CH2), 0.89 (t, 3H, J=7,3 Hz, CH3). IR (cm 1): 2933, 1622, 1530, 1408, 1353, 1279, 1181, 1020, 824.
Example 8. Preparation of compounds of general formula (I), wherein Y = H, n = 2 and m = 2, from compounds wherein m = 0
Figure imgf000032_0001
Figure imgf000032_0002
3-(4-methoxy-3-nitrophenyl)-l-(4,4-dioxo-6-propoxybenzo[^][l,4]-oxathian-7-yl)propane
3-(4-Methoxy-3-nitrophenyl)-l-(6-propoxy-2,3-dihydrobenzo[^][l,4]-oxathiin-7-yl)propane (1,0 g, 2,48 mmol), prepared as described in Example 7, was dissolved in acetic acid (15 ml), 30 % hydrogen peroxide (12 ml) was added, and the mixture was stirred at 75 °C for 5 hours. Next, the mixture was cooled down, diluted with water (20 ml), and extracted with ethyl acetate (2 x 40 ml). The organic layer was washed with sodium carbonate solution, brine, dried over sodium sulfate, and evaporated. The residue was purified on silica gel column in methylene chloride - ethyl acetate 10 : 1 solution, and next crystallized from methanol to give 3-(4-methoxy-3-nitrophenyl)-l-(4,4-dioxo-6-propoxybenzo[b][l,4]- oxathian-7-yl)propane (0,85 g, 79 %), m.p. 104-107 °C. 1H NMR (DMSO-d6) δ 7.68 (d, IH, J=2,2 Hz, H-2'), 7.46 (dd, IH, Ji=8,7 Hz, J2=2,3 Hz, H-6'), 7.24 (d, IH, J=8,5 Hz, H-5'), 7.02 (s, IH, H-8 lub H-5), 6.89 (s, IH, H-8 lub H-5), 4.66 (t, 2H, J=5,3 Hz, OCH2), 3.88 (t, 5H, J=6,3 Hz, OCH3, OCH2), 3.74 (t, 2H, J=5,3 Hz, SCH2), 2.61 (t, 2H, J=7,3 Hz, CH2), 2.56 (t, 2H, J=7,5 Hz, CH2), 1.81 (m, 2H, CH2), 1.65 (m, 2H, CH2), 0.90 (t, 3H, J=7,3 Hz, CH3). IR (cm"1): 2933, 1621, 1525, 1296, 480.
Example 9. Preparation of compounds of general formula (I), wherein Y = H, n = 1 and m = 2, from compounds wherein m = 0
Figure imgf000032_0003
l-(4-methoxy-3-nitrophenyl)-3-(3,3-dioxo-5-propoxybenzo[^][l,4]-oxathiol-6-yl)propane
1 -(4-Methoxy-3 -nitrophenyl)-3 -(6-propoxybenzo [b] [1,4] -oxathiol-6-yl)propane ( 1 ,445 g, 3,7 mmol), prepared as described in Example 7, was dissolved in acetic acid (20 ml), the solution was warmed up 75 °C, and 30 % hydrogen peroxide (10 ml) was added portionwise, with stirring. The mixture was stirred at 75 °C until the reaction ended, the precipitated solid was filtered off, and washed with hot methanol to give 3-(4-methoxy-3-nitrophenyl)-l-(3,3- dioxo-6-propoxybenzo[£][l,4]-oxathiol-6-yl)propane. NMR (500 MHz, DMSO-d6): δ 7,69 (d, 1H, J = 2,3 Hz, H-2'), 7,48 (dd, 1H, = 8,7 Hz, J2 = 2,3 Hz, H-6'), 7,29 (s, 1H, H-4), 7,25 (d, 1H, J = 8,5 Hz, H-5), 5,31 (s, 2H, H-2), 3,94 (t, 2H, J = 6,2 Hz, OCH2), 3,87 (s, 3H, OCH3), 2,61, 4 H, 2 x CH2), 1,83 (m, 2H, CH2), 1,66 (m, 2H, CH2), 0,91 (t, 3H, J = 7,3 Hz).
Example 10. Preparation of compounds of general formula (I), wherein Y = H, and one of the substituents X = NH2
Figure imgf000033_0001
General procedure:
A suitable starting compound, prepared as described above in Examples 7 - 10, is reduced with a reducing agent, which is suitable for reduction of nitro group, using procedures generaly known in the state of the art, and the obtained product is isolated using generaly known methods. For example, the substrate is dissolved in an organic solvent, such as ethyl acetate and reacted with hydrogen in the presence of palladium catalyst, and the obtained product is isolated on silica gel chromatography column.
Figure imgf000033_0002
Using the described above procedure for preparation of compounds of general formula (I), wherein Y = H, and one of the substituents X = NH2, 3-(4-methoxy-3-nitrophenyl)-l-(6- propoxybenzo[ ][l,4]-oxathian-7-yl)propane (315 mg, 0,72 mmol), prepared as described in Example 7, was dissolved in ethyl acetate (15 ml), 10 % palladium on charcoal (770 mg), was added, and the mixture was stirred at room temperature, under hydrogen, for 19 hours. Next, the mixture was filtered on silica gel column in ethyl acetate, the filtrate was evaporated to give crude product. The product was purified on silica gel column in methylene chloride - ethyl acetate 50 : 1 solution to give a colorless oil (189 mg, 70 %). The oil was dissolved in diethyl ether and a solution of hydrochloride in diethyl ether was added. The precipitated solid was filtered off, washed with diethyl ether and dried, to give 3-(3- amino-4-methoxyphenyl)-l-(6-propoxybenzo[^][l,4]-oxathian-7-yl)propane hydrochloride (168 mg). NMR (500 MHz, DMSO-d6): δ 9,87 (bs, 3H, NH3 +), 7,20 (s, 1H, H-2'), 7, 14 (d, 1H, J = 8,5 Hz, H-6'X 7,08 (d, 1H, J = 8.5Hz, H-5'), 6,59 (s, 1H, H-8, 6,55 (s, 1H, H-5), 4,24 (m, 2H, H-2), 3,84 (s, 3H, OCH3), 3,79 (t, 2H, J = 6,2 Hz, OCH2), 3,12 (m, 2H, H-3), 2,51(t, 2H, J = 7,6 Hz, CH2), 2,44 (t, 2H, J = 7.8 Hz, CH2), 1,72 (m, 2H, CH2), 1,64 (m, 2H, CH2), 0.92 (t, 3H, J = 7,5 Hz, CH3).
Using the described above procedure for preparation of compounds of general formula (I), wherein Y = H, and one of the substituents X = NH2, and demonstrated for compound AMG-485, the following compounds were obtained:
Figure imgf000034_0001
-amino-4-methoxyphenyl)-l-(4,4-dioxo-6-propoxybenzo[^][l,4]-oxathian-7-yl)propane, a clorless solid (0,503 g, 68 %), m.p. 70-79°C. 1H NMR (DMSO-d6) δ 7.04 (s, 1H, H-5), 6.87 (s, 1H, H-8), 6.65 (d, 1H, J=8,2 Hz, H-5'), 6.43 (d, 1H, J=2,0 Hz, H-2'), 6.30 (dd, 1H, Ji=7,9 Hz, J2=2,2 Hz, H-6'), 4.67 (m, 2H, OCH2), 4.57 (s, 2H, NH2), 3.91 (t, 2H, J=6,2 Hz, OCH2), 3.75 (m, 2H, SCH2), 3.69 (s, 3H, OCH3), 2.54 (t, 2H, J=7,5 Hz, CH2), 2.39 (t, 2H, J=7,5 Hz, CH2), 1.71 (m, 4H, 2xCH2), 0.95 (t, 3H, J=7,4 Hz, CH3). IR (cm-1): 3468, 3379, 1616, 1515, 1492, 1286, 1227, 1140, 477.
Figure imgf000034_0002
l-(3-amino-4-methoxyphenyl)-3-(3,3-dioxo-5-propoxybenz[<i][l,3]oxathiol-6-yl)propane, m.p. 96-100°C. 1H NMR (DMSO-d6) δ 7.29 (s, 1H, H-4), 7.11 (s, 1H, H-7), 6.64 (d, 1H, J=8,0 Hz, H-5'), 6.43 (d, 1H, J=2, l Hz, H-2'), 6.31 (dd, 1H, J1=8,2 Hz, J2=2,l Hz, H-6'), 5.31 (s, 2H, H-2), 4.57 (s, 2H, NH2), 3.95 (t, 2H, J=6,l Hz, OCH2), 3.69 (s, 3H, OCH3), 2.60 (t, 2H, J=7,6 Hz, CH2), 2.40 (t, 2H, J=7,7 Hz, CH2), 1.71 (t, 4H, J=7,l Hz, 2xCH2), 0.94 (t, 3H, J=7,3 Hz, CH3). IR (cm"1): 3417, 3343, 1621, 1516, 1466, 1300, 1231, 1153, 870.
Example 12. Preparation of compounds of general formula (I), wherein Y = NH2, using reductive amination method
Figure imgf000035_0001
Figure imgf000035_0002
3-(3-fluoro-4-methoxyphenyl)-l-(7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6-yl)propan- 1- amine
3-(3-Fluoro-4-methoxyphenyl)-l-(7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6- yl)propan-l-one (460 mg, 1,17 mmol), prepared as described in Example 1, ammonium acetate (1006 mg, 13,75 mmol), and sodium cyjanoborohydride (62 mg, 1 mmol) in methanol (10 ml) were strred at reflux temperature for 22 hours. The mixture was cooled down, acidified with diluted hydrochloric acid, and washed with diethyl ether. The aqueous layer was alkalized with diluted sodium hydroxide and extracted with methylene chloride. The organic layer was washed with water, dried (sodium sulfate) and evaporated. The residue was purified on silica gel column in methylene chloride - methanol 10 : 1 solution, to give colorless oil (285 mg, 62 %). The product was dissolved in anhydrous ethanol (2 ml) and solution of hydrochloride in diethyl ether (0.7 ml) was added. The solvents were evaporated, and the residue was crystallized from ethanol - water to give a colorless solid of 3-(3-fluoro-4-methoxyphenyl)-l-(7-propoxy-2,3-dihydrobenzo[b][l,4]oxathiin-6-yl)propan- 1-amine hydrochloride (180 mg, 36 %), m.p. 160 - 161 °C. NMR (500 MHz, DMSOd6): δ 8,30 (bs, 3 H, CNH3 +), 7,17 (s, 1 H, H-5), 7,04 (t, 1 H, J = 8,7 Hz, H-5'), 6,99 (d, 1 H, J = 2,7 Hz, H-2'), 6,89 (d, 1 H, J = 8,2 Hz, H-6'), 6,52 (s, 1 H, H-8), 4,35 (m, 3 H, H-2 + CH), 3,84 (t, 2 H, J = 6,3 Hz, OCH2), 3,78 (s, 3 H, OCH3), 3,15 (m, 2 H, H-3), 2,45 (bm, 2 H, CH2Ph), 2,16 (m, 1 H, CHCHNH), 2,03 (m, 1 H, CHCHNH), 1,65 (m, 2 H, CH2), 0,88 (t, 3 H, J = 7,3 Hz, CH3). IR (KBr, cm"1): 3435, 2922, 1613, 1519, 1275.
Example 13. Preparation of compounds of general formula (I), wherein Y = NH2, via oximes
Figure imgf000036_0001
Step 1.
3-(3-Fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-
1-one (2,98 g, 7,3 mmol), prepared as described in Example 1, hydroxylamine hydrochloride
(1,529 g, 22 mmol) and pyridine (1,2 ml, 14,8 mmole) in ethanol (20 ml) were stirred at reflux temperature for 1,5 hour. The mixture was slowly diluted with water (80 ml), the precipitated solid was filtered off, washed with water, and crystallized from ethanol to give 3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- one oxime, (2,234 g, 72 %). NMR demonstrated that this is a mixture of two isomers. NMR (500 MHz, DMSO-d6): δ 11,42 (s, 1 H, OH isomer A), 10,74 (s, 1 H, OH isomer B), 7,46 (s, 1 H, H-4, isomer A), 7,45 (s, 1 H, H-4, isomer B), 6,92 - 7,08 (m, 8 H, aromatic), 6,90 (s, 1 H, H-7, isomer A), 6,84 (d, 1 H, J = 8,3 Hz, H-6', isomer A), 5,37 (s, 1 H, H-2, isomer B), 5,36 (s, 1 H, H-2, isomer A), 4,02 (t, 2 H, J = 6,4 Hz, OCH2, isomer A), 3,96 (t, 2 H, J = 6,2 Hz, OCH2, isomer B), 3,77 (s, 3 H, OCH3, isomer B), 3,76 (s, 3 H, OCH3, isomer A), 2,90 (m, 2 H, NCCH2, isomer A), 2,68 (s, 4 H, NCCH2 + CH2Ph, isomer B), 2,61 (m, 2 H, CH2Ph), 1,6 - 1,8 (m, 4 H, CH2, isomers A and B), 0,94 (m, 6 H, CH3, isomers A and B). IR (KBr, cm"1): 3429, 1521, 1441, 1298, 1134, 1029.
Step 2
3-(3-Fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan- 1-one oxime (700 mg, 1,65 mmol) and zinc dust (700 mg, 10,7 mmol) in acetic acid (10 ml) were stirred at reflux temperature for 2 hours. The mixture was cooled down, diluted with water, alkalized with sodium bicarbonate (22 g), and extracted with ethyl acetate (200 ml). The organic layer was washed with water, brine, dried with sodium sulfate, and evaporated. The residue was purified on silica gel column in methylene chloride - methanol 20 : 1 solution to give a colorless solid (400 mg). The solid was suspended in anhydrous methanol (3 ml), 2N solution of hydrochloride in diethyl ether (2,5 ml) was added, and the obtained clear solution was diluted with diethyl ether (50 ml). The precipitated solid was filtered off, and washed with diethyl ether to give 3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5- propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l-amine hydrochloride, 320 mg (43 %). NMR (500 MHz, D20): δ 7,05 (s, 1 H, H-4), 6,98 (s, 1 H, H-7), 6,71 (t, 1 H, J = 8,9 Hz, H-5'), 6,62 (d, 1 H, J = 13,2 Hz, H-2'), 6,55 (d, 1 H, J = 8,6 Hz, H-6'), 5,12 (s, 2 H, H-2), 4,41 (m, 1 H, H-a), 3,79 (m, 2 H, OCH2), 3,67 (s, 3 H, OCH3), 2,62 (m, 1 H, H-b), 2,41 (m, 2 H, H- c), 2,21 (m, 1 H, H-b), 1,65 (m, 2 H, CH2), 0,86 (t, 3 H, J = 7,4 Hz, CH3). IR (KBr, cm"1): 3424, 2961, 2922, 2853, 1604, 1522, 1316, 1178, 1156, 1040.
Analogously, the following compounds were prepared:
Figure imgf000037_0001
-amino-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2-methoxyphenol.
NMR (500 MHz, DMSO-d6): δ 8,73 (s, 1 H, OH), 7,38 (s, 1 H, H-4), 7,27 (s, 1 H, H-7), 6,75 (d, 1 H, J = 8,1 Hz, H-5'), 6,56 (d, 1 H, J = 1,8 Hz, H-2'), 6,50 (dd, 1 H, = 8,1 Hz, J2 = 1,8 Hz, H-6'), 5,31 (s, 2 H, H-2), 4,10 (m, 1 H, Ha), 3,92 (m, 2 H, OCH2), 3,69 (s, 3 H, OCH3), 2,54 (m, 1 H, He), 2,43 (m, 1 H, He), 1,92 (bs, 2 H, NH2), 1,77 (m, 1 H, Hb), 1,66 (m, 2 H, CH2), 1,58 (m, 1 H, Hb), 0,92 (t, 3 H, J = 7,4 Hz, CH3
Figure imgf000038_0001
5-(3-arnino-3-(4,4-dioxo-7-propoxy-2,3-di ydrobenzo[b][l,4]oxathiin-6-yl)propyl)-2- methoxyphenol. NMR (500 MHz, DMSO-d6): δ 8,73 (s, 1 H, OH), 7,72 (s, 1 H, H-5), 6,75 (d, 1 H, J = 8,2 Hz, H-5'), 6,56 (d, 1 H, J = 1,9 Hz, H-2'), 6,50 (m, 2 H, H-8 + H-6'), 4,71 (m, 2 H, H-3), 4,01 (m, 1 H, Ha), 3,91 (m, 2 H, OCH2), 3,70 (m, 5 H, OCH3 + H-2), 2,5 (m, He, under DMSO), 2,41 (m, 1 H, He), 1,87 (bs, 2 H, NH2), 1,75 (m, 1 H, Hb), 1,68 (m, 2 H, CH2), 1,59 (m, 1 H, Hb), 0,92 (t, 3 H, J = 7,2 Hz, CH3).
Figure imgf000038_0002
(2S)-2-amino-N-(5-(3-amino-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2- methoxyphenyl)-4-methylpentanamide. NMR (500 MHz, D20) (spectrum for hydrochloride): δ 7,13 (s, 1 H), 7,12 (s, 1 H), 7,07 (s, 1 H), 7,04 (s, 1 H), 6,92 (s, 1 H), 6,89 (s, 1 H), 6,72 (s, 2 H), 6,71 (s, 2 H), 5,10 (m, 4 H), 4,45 (m, 2 H), 4,10 (m, 2 H), 3,75 - 3,85 (m, 4 H), 3,65 (s, 6 H), 2,65 (m, 2 H), 2,40 (m, 4 H), 2,25 (m, 2 H), 1,55 - 1,75 (m, 10 H), 0,85 (m, 18 H).
AMG-435
Figure imgf000038_0003
A side product in synthesis of AMG-434 (above) formed in case of prolonged zinc reduction, (2S)-2-acetamido-N-(5-(3-amino-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol- 6-yl)propyl)-2-methoxyphenyl)-4-methylpentanamide. NMR (500 MHz, DMSO-d6): δ 8,99 (2 x s, 21 H, NHCO), 8,24 (m, 1 H, NHCO), 7,83 (s, 1 H, H-2'), 7,38 (s, 1 H, H-7), 7,27 (s, 1 H, H-4), 6,90 (d, 1 H, J = 8,2 Hz, H-5'), 6,84 (d, 1 H, J = 8,2 Hz, H-6'), 5,33 (d, 1 H, J = 10,0 Hz, H-2), 5,30 (d, 1 H, J = 10,0 Hz, H-2), 4,43 (m, 1 CH), 4,11 (m, 1 H, CH), 3,92 (m,
2 H, CH2), 3,77 (s, 3 H, OCH3), 2,60 (m, 1 H, CH), 2,50 (m, 1 H, CH), 2,13 (bs, 2 H, NH2), 1,88 (s, 3 H, COCH3), 1,79 (m, 1 H, CH), 1,63 (m, 4 H, 2 x CH + CH2), 1,52 (m, 2 H, CH2), 0,90 (m, 6 H, 2 x CH3 ), 0,85 (d, 3 H, J = 6,5 Hz, CH3).
MTT cytotoxicity assay
MTT assay is a colorimetric assay used for estimation of cells proliferation and viability as well as cytotoxicity of the substance, for the cells. It consists in decomposition of the yellow tetrazolium salt MTT (methyl 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazole bromide) to insoluble in water purple dye formazan, by the mitochondrial succinic-tetrazole reductase. MTT reduction occurs in living cells only. Data analysis consists in determination of concentration of the test compound wherein 50 % reduction in the number of cells in the treated population occurs, in comparison to to the control cells. Results were analyzed using GraphPad Prism 4.0.
The assay was performed according to literature description (Celis, J.E., (1998). Cell biology, a laboratory handbook, second edition, Academic Press, San Diego; Yang, Y., Koh, L.W., Tsai, J-H., (2004), Involvement of viral and chemical factors with oral cancer in Taiwan, Jpn J Clin Oncol, 34(4)176-183).
Human cervix carcinoma cells HeLa (ATCC# CCL-2) were maintained in MEM medium (HyClone, Logan, UT, USA) supplemented with 10 % fetal calf serum (HyClone, Logan, UT, USA), 2mM L-glutamine and antibiotics (penicillin 100 U/ml and streptomycin 100 mg/ml (HyClone, Logan, UT, USA) at temperature 37 °C, under atmosphere of air supplemented with 5 % of C02.
Human colonic epithelial cells HCT-116 (ATCC# CCL-247) were maintained in McCoy's medium (HyClone, Logan, UT, USA) supplemented with 10 % fetal calf serum (HyClone, Logan, UT, USA), 2mM L-glutamine and antibiotics (penicillin 100 U/ml and streptomycin 100 mg/ml (HyClone, Logan, UT, USA) at temperature 37 °C, under atmosphere of air supplemented with 5 % of C02.
Human lung adenocarcinoma epithelial cells A549 (ATCC# CCL-185) were maintained in RPMI1640 medium (HyClone, Logan, UT, USA) supplemented with 10 % fetal calf serum (HyClone, Logan, UT, USA), 2mM L-glutamine and antibiotics (penicillin 100 U/ml and streptomycin 100 mg/ml (HyClone, Logan, UT, USA) at temperature 37 °C, under atmosphere of air supplemented with 5 % of C02.
Cells were subjected to routine checkup for the presence of Mycoplasma by PCR using commercially available Venor®GeM Mycoplasma PCR Detection Kit (Minerva Biolabs, Berlin, Germany).
The cells culture was diluted with the medium to a specified density (104 - 105 cells per 100 μΐ). Then 100 μΐ of appropriately diluted cell suspension was applied in 96-well plate in triplicates, The cells thus prepared were incubated for 24 hours at 37 °C in 5 % C02, then to the cells (in 100 μΐ of medium) another 100 μΐ of culture medium containing different concentrations of test compounds was added. The cells were incubated with tested compounds for subsequent 72 hours, what corresponds to 3 - 4 times of cell division. Then to the medium with test compounds 20 μΐ of MTT working solution [5 mg/ml] was added and incubated for 3 hours at 37 °C in 5 % C02. Then, medium with the MTT solution was removed, and formazan crystals were dissolved in 100 μΐ of DMSO. After mixing, the absorbance was measured at a wavelength of 570 nm (reference filter 690 nm). Results of the test are presented in Table 1 as IC50 [μΜ].
Table 2 presents evaluation of anticancer activity of compound AMG-415 against murine Colon 26 carcinoma, inoculated subcutaneously to BALB/C mice.
Table 3 presents evaluation of anticancer activity of compound AMG-432 against murine Colon 26 carcinoma, inoculated subcutaneously to BALB/C mice.
Table 1
Compound no A549 HCT116 HeLa
Compounds of general formula IIA
AMG-391 0,019 0,020 0,020
AMG-407 0,075 0,025 0,021
AMG-421 0,156 0,241 0,085
AMG-395 0,356 0,207 0,097 AMG-401 > 4 > 4 1,427
AMG-409 4,20 1,95 1,52
AMG-482 1,70 0,826 1,161
AMG-479 0,15 0,0093 0,045
AMG-396 0,054 0,021 0,012
AMG-397 3,06 2,147 0,257
AMG-398 0,030 0,001 0,005
AMG-403 0,023 0,002 0,004
AMG-414 0,037 0,012 0,013
AMG-405 0,008 0,002 0,004
AMG-415 0,004 0,002 0,001
AMG-419 2,50 1,89 1,64
AMG-417 2,71 0,179 0,200
AMG-420 0,0075 0,0024 0,001
Compounds of general formula IIB
AMG-402 > 4 > 4 > 4
AMG-399 0,018 0,014 0,0033
AMG-430 0,016 0,018 0,002
AMG-431 0,021 0,026
AMG-432 0,028 0,037
Compounds of general formula IID
AMG-485 68.91 30.66 63.00
AMG-486 6.08 5.96 5.41
AMG-483 6.9 6.36 5.25
AMG-484 4.98 3.45 5.61
AMG-487 0.273 0.117 0.048
AMG-488 0.416 0.214 0.158
Compounds of general formula IIC
AMG-428 > 4 > 4
AMG-412 > 4 > 4 AMG-433 0.179 0.192
AMG-434 0.363 0.462
AMG-435 >4 >4
AMG-413 0.198 0.244 0.158
Table 2
Figure imgf000043_0001
Table 3 Body weight Mean Tumor Mean Tumor Number of change from tumor growth tumor growth animals per the size on inhibition size on inhibition experiment /
Group
beginning of the 14th after 14th the 15th after 15th day Number of name
treatment day day [%] day [%] dead animals (from day 1 [mg] [mg]
to 14)
CONTROL
-2,10 545,04 695,59 20/7 female
AMG 432
-2,10 552,37 -1 755,92 -9 8/5
12,5 mg/kg
AMG 432
-1,10 520,18 5 814,25 -17 8/0
25mg/kg
AMG 432
-0,70 336,42 38 550,31 21 8/0
50 mg/kg
AMG 432
-1,00 288,70 47 395,71 43 8/0 lOOmg/kg

Claims

Claims
1. Compounds of general formula (I),
Figure imgf000045_0001
(I)
wherein
A and B are linked together and form a a moiety selected from -0-(CH2)n-S(0)m-, -S(0)m- (CH2)„-0- or -0-(CH2)n-0- or one of A and B is -S(0)m-Ci-C6-alkyl, and the second is selected from a group consisting of OH and -0-Ci-C6-alkyl;
R is H, Ci-Ce-alkyl, CO-Ci-C6-alkyl, or -(CH2)p-NR1R2, wherein
R 1 and R 2" are independently of each other, H, Ci-C6-alkyl, or
R 1 and R 2" are linked together by a polymethylene linker -(CH2)q-, to form along with the nitrogen atom to which they are attached a five or six- membered ring, wherein one of carbon atoms may be optionally replaced by O, N, or S.
Y is: O, H, OH, NH2
1 2 3 are, independently of each other, H, halogen atom, OH, -0-Ci-C6alkyl, -O-CO- Ci-C6alkyl, -0-Ci-C6alkyl(N(Ci-C6 alkyl)2), 0-PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl m= 0, l, or 2 n= 1 or 2; p=2 to 6 q= 4 or 5, and their pharmaceutically acceptable salts
2. Compounds according to Claim 1 described by formula (IIA)
Figure imgf000046_0001
(IIA)
wherein A, B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
3. Compounds according to Claim 1 described by formula (IIB)
Figure imgf000046_0002
(ΠΒ)
wherein A, B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
4. Compounds according to Claim 1 described by formula (IIC)
Figure imgf000046_0003
(IIC)
wherein A, B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
5. Compounds according to Claim 1 described by formula (IID)
Figure imgf000046_0004
(IID) wherein A, B, R, X 1 , X2 , X 3 have the same meanings as defined for general formula (I).
6. Compounds according to Claim 1 described by formula (IV)
Figure imgf000047_0001
(IV) wherein A, B, R have the same meanings as defined for general formula (I), X is H, halogen atom, OH, -0-Ci-C6alkyl, -0-CO-Ci-C6alkyl, -0-Ci-C6alkyl(N(Ci- C6alkyl)2), 0-PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl
7. Compounds according to Claim 1 described by formulas VA-VD, VIA-VID, VIIA- VIID, VIIIA-VIIID:
Figure imgf000047_0002
Figure imgf000048_0001
wherein R and m have the same meanings as defined above for general formula (I), X is H, halogen atom, OH, -0-Ci-C6alkyl, -0-CO-Ci-C6alkyl, -0-Ci-C6alkyl(N(Ci- C6alkyl)2), 0-PO(OH)2, N02, NH2 or NHR3, wherein R3 is Ci-C6alkyl.
8. Compound selected from a group consisting of:
3 -(3 -hydroxy-4-methoxyphenyl) - 1 -(7 -propoxy-2,3 -dihydrobenzo [b] [ 1 ,4] oxathiin-6- yl)propan-l-one (AMG-391);
3 -(3 -amino-4-methoxyphenyl) - 1 -(7 -propoxy-2,3 -dihydrobenzo [b] [1,4] oxathiin-6-yl)propan- 1-one (AMG-407);
(S )-2-amino-N-(2-methoxy-5 -(3 -oxo-3 -(7-propoxy-2,3 -dihydrobenzo [b] [ 1 ,4] oxathiin-6- yl)propyl)phenyl)-4-methylpentanamide (AMG-421);
3-(3-fluoro-4-methoxyphenyl)-l-(7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6-yl)propan- 1-one (AMG-395);
3 -(3 -hydroxy-4-methoxyphenyl) - 1 -(4,4-dioxo-7-propoxy-2,3 -dihydrobenzo [b] [ 1 ,4] oxathiin- 6-yl)propan- 1-one (AMG-401); 3-(3-amino-4-methoxyphenyl)-l-(4,4-dioxo-7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6- yl)propan-l-one (AMG-409);
3-(3-amino-4-methoxyphenyl)-l-(6-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-7-yl)propan- 1-one (AMG-482);
3-(3-amino-4-methoxyphenyl)-l-(4,4-dioxido-6-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin- 7-yl)propan-l-one (AMG-479);
3 -(3 -hydroxy-4-methoxyphenyl) - 1 -(5 -propoxybenzo [d] [1,3] oxathiol-6-yl)propan- 1 -one (AMG-396);
3-(3-fluoro-4-methoxyphenyl)-l-(5-methoxybenzo[<i][l,3]oxathiol-6-yl)propan-l-one
(AMG-397);
3-(3-hydroxy-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-
1- one (AMG-398);
2- methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[d][l,3]oxathiol-6-yl)propyl)phenyl acetate (AMG-403); sodium 2-methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propyl)phenyl phosphate (AMG-414);
3- (3-amino-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- one (AMG-405);
(S)-2-amino-N-(2-methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propyl)phenyl)-4-methylpentanamide (AMG-415);
(S)-tert-butyl l-(2-methoxy-5-(3-oxo-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propyl)phenylamino)-4-methyl- l-oxopentan-2-yl carbamate (AMG-419);
3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- one (AMG-420);
5-(3-hydroxy-3-(4,4-dioxo-7-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-6-yl)propyl)-2- methoxyphenol (AMG-402);
5-(3-hydroxy-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2-methoxyphenol (AMG-399); 3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- ol (AMG-430);
3 -(3 -hydroxy-3 -(3 ,3 -dioxo-5-propoxybenzo [d] [ 1 ,3 ] oxathiol-6-yl)propyl)-2-methoxyaniline (AMG-431);
(2S)-2-amino-N-(5-(3-hydroxy-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-
2- methoxyphenyl)-4-methylpentanamide (AMG-432) ;
3- (4-methoxy-3-nitrophenyl)-l-(6-propoxybenzo ^7[l54]-oxathian-7-yl)propane; l-(4-methoxy-3-nitrophenyl)-3-(5-propoxybenzo ^7[l54]-oxathiol-6-yl)propane; 3-(4-methoxy-3-nitrophenyl)-l-(4,4-dioxo-6-propoxybenzo/^7[l54]-oxathian-7-yl)propane;
1- (4-methoxy-3-nitrophenyl)-3-(3,3-dioxo-5-propoxybenzo/^7[l54]-oxathiol-6-yl)propane;
2- methoxy-5-(3-(6-propoxy-2,3-dihydrobenzo[^][l,4]oxathiin-7-yl)propyl)aniline (AMG- 485);
(S)-2-amino-N-(2-methoxy-5-(3-(6-propoxy-2,3-di ydrobenzo[&][l,4]oxathiin-7- yl)propyl)phenyl)-4-methylpentanamide (AMG-486);
7-(3-(3-amino-4-methoxyphenyl)propyl)-6-propoxy-2,3-dihydrobenzo[^][l,4]oxathiine 4,4- dioxide (AMG-483);
(S)-2-amino-N-(5-(3-(4,4-dioxido-6-propoxy-2,3-di ydrobenzo[^][l,4]oxathiin-7- yl)propyl)-2-methoxyphenyl)-4-methylpentanamide (AMG-484);
6-(3-(3-amino-4-methoxyphenyl)propyl)-5-propoxybenzo[<i][l,3]oxathiole 3,3-dioxide
(AMG-487);
(S)-2-amino-N-(5-(3-(3,3-dioxido-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2- methoxyphenyl)-4-methylpentanamide (AMG-488);
3- (3-fluoro-4-methoxyphenyl)-l-(7-propoxy-2,3-dihydrobenzo[b][l,4]oxathiin-6-yl)propan- 1-amine (AMG-428);
5-(3-amino-3-(4,4-dioxo-7-propoxy-2,3-dihydrobenzo[¾[l,4]oxathiin-6-yl)propyl)-2- methoxyphenol (AMG-412);
3-(3-fluoro-4-methoxyphenyl)-l-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propan-l- amine (AMG-433); (2S)-2-amino-N-(5-(3-amino-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2- methoxyphenyl)-4-methylpentanamide (AMG-434);
(2S)-2-acetamido-N-(5-(3-amino-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6- yl)propyl)-2-methoxyphenyl)-4-methylpentanamide (AMG-435);
5-(3-amino-3-(3,3-dioxo-5-propoxybenzo[<i][l,3]oxathiol-6-yl)propyl)-2-methoxyphenol (AMG-413).
9. Pharmaceutical composition containing compounds as defined in Claims 1 to 8 and a pharmaceutically acceptable carrier.
10. Compounds as defined in Claims 1 to 8 for use as a drug.
11. Compounds as defined in Claims 1 to 8 for use in therapy of cancer.
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