JP4913056B2 - Substituted chroman derivatives, pharmaceuticals, and therapeutic uses - Google Patents

Description

  The present invention relates to certain novel chroman derivatives and salts and derivatives thereof, compositions containing them, methods for their preparation and methods for their use as therapeutic agents (especially anticancer agents and selective chemotherapeutic agents).

  Over 700 natural isoflavones are known, some of which have biological properties that can be therapeutically effective.

  US Pat. No. 5,726,202 generally discloses certain isoflavan compounds (particularly 3,4-diarylchromans and centchromans) for treating benign prostatic hypertrophy.

  International Publication WO 01/17986 discloses specific isoflavan compounds.

SUMMARY OF THE INVENTION Surprisingly, the inventors have found a novel group of compounds of general formula (I) that exhibit important therapeutic activities including strong anticancer activity, chemotherapy selectivity and cancer radiosensitization. .

According to an aspect of the present invention, there is provided a compound of the following general formula (I) or a salt or derivative thereof, and a pharmaceutically acceptable salt thereof:

[Where:
R ₁ is hydrogen, hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 fluoroalkyl, or optionally one or more hydroxy, C _1-6 alkyl _optionally substituted by chloro, bromo, iodo or NR ₁₀ R ₁₁ groups,
Drawing " --- " and R ₂ together represent a double bond, or drawing " --- " represents a single bond and R ₂ is hydrogen, hydroxy, NR ₁₀ R ₁₁ , C _{1- 3} alkoxy, C _1-3 fluoroalkyl, halo or optionally one or more hydroxy, chloro, bromo, iodo or NR ₁₀ C _1-3 alkyl optionally substituted by R ₁₁ groups,
R ₃ is hydrogen, hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 fluoroalkyl, C _2-6 alkenyl, COOR ₁₂ , COR ₁₃ , (O) _n C _1-4 alkylene NR ₁₄ R ₁₅ , or C _1-6 alkyl optionally substituted with one or more hydroxy, chloro, bromo, iodo or NR ₁₀ R ₁₁ groups;
R _4, R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are independently hydrogen, hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 Fluoroalkyl, C _2-6 alkenyl, COOR ₁₂ , COR ₁₃ , or C _1-6 alkyl optionally substituted with one or more hydroxy, chloro, bromo, iodo or NR ₁₀ R ₁₁ ;
R ₁₀ , R ₁₁ and R ₁₂ are independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or trialkylsilyl;
R ₁₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or NR ₁₀ R ₁₁ ,
n represents 0 or 1,
R ₁₄ and R ₁₅ independently represent hydrogen or C _1-6 alkyl, or together NR ₁₄ R ₁₅ represents a 5 or 6 membered heteroaromatic or heterocyclic group (provided that when R ₁ is hydrogen, and "---" is a bond, R ₂ is not hydrogen)].

  According to another aspect of the present invention, there is provided a process for preparing a compound of formula (I).

  According to another aspect of the present invention, one or more compounds of formula (I) or a pharmaceutically acceptable salt or derivative thereof are combined with one or more pharmaceutical carriers, excipients, adjuvants and / or dilutions. A pharmaceutical composition comprising the agent is provided.

  Thus, according to another aspect of the present invention there is provided the use of a compound of formula (I) in therapy (especially chemotherapy) and as a radiosensitizer.

  According to another aspect of the invention, there is provided a method for the treatment, prevention or amelioration of a disease or disorder, which method comprises an effective amount of one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof or It includes administering the derivative to a subject, optionally with a carrier and / or excipient.

  According to another aspect of the invention, there is provided an agent for treating, preventing or ameliorating a disease or disorder, such agent comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof or Including derivatives.

Detailed Description of the Invention The inventors have found that compounds of general formula (I) exhibit unexpected and unexpected biological and pharmaceutical properties.

  The compounds of formula (I) of the present invention are believed to have an advantageous toxicity profile for normal cells and good bioavailability. Surprisingly, the compounds of the present invention show anticancer activity, which is much better than or at least comparable to known cancer therapeutics.

  Compounds of formula (I) are cytostatic and cytotoxic to a wide range of human and animal derived cancer cells. By cancer cell is meant a cell that exhibits malignant characteristics and is distinguished from non-cancerous cells by uncontrollable growth and behavior, which is usually ultimately life-threatening unless treatment is successful. Cancer cells that have been found to be responsive to compounds of formula (I) are of epithelial origin (eg, prostate cancer, ovarian cancer, cervical cancer, breast cancer, gallbladder cancer, pancreatic cancer, colon cancer). Rectal cancer, kidney cancer and non-small lung cancer cells), mesenchymal (eg, melanoma, mesothelioma and sarcoma cancer cells), and nerve derived (eg, glioma cancer cells). .

  It is very unusual and surprising to find a group of related compounds that exhibit such potent cytotoxicity against cancer cells. Furthermore, the compounds according to the invention are also considered to be less toxic to non-cancerous cells such as keratinocytes derived from human foreskin. Such selectivity for cancer cells is highly specific and unexpected.

  Advantageously, the compounds of formula (I) are cytotoxic to cancer cells that are well recognized to be insensitive to standard anticancer agents. For example, it is very rare and unexpected to find such potent activity against cancers such as bile duct cancer, pancreatic adenocarcinoma and melanoma that are very resistant to known anticancer agents.

Conveniently, the compounds of formula (I) also appear to increase the sensitivity of cancer cells to radiation, which means that these compounds require the gamma radiation needed to kill cancer cells. It means reducing the dose or changing the cancer cells from a radiation resistant to a radiation sensitive state.
Furthermore, the compounds of formula (I) are believed to have chemotherapeutic sensitizing activity, ie increase the cytotoxicity of the chemotherapeutic agent (especially against cancer cells) and / or chemotherapeutic cells Change from resistance to chemosensitivity.

  The compounds of the invention also provide the property of protecting non-cancerous cells from chemotherapeutic agents and / or radiation. This has important therapeutic implications. This is because the traumatic side effects of chemotherapy and radiation therapy are caused by the toxicity of conventional treatments on non-cancerous cells.

  The above characteristics provide important clinical advantages.

  The radiation and / or chemotherapeutic protective properties of the compounds of the present invention can be utilized to protect healthy individuals from the effects of radiation and / or chemical toxins or to reduce their effects.

The above characteristics provide important clinical advantages.
The invention also slows the growth rate of tumors by treatment with the compound of formula (I) alone and / or in combination with each other and / or in combination with other anticancer agents and / or in combination with radiation therapy. Provided is the use of a compound of formula (I) for treating a cancer patient by reducing the size of a tumor.

In general, in the compounds of formula (I) of the present invention, the substituents R ₈ and R ₉ are assigned as shown below:

In general, in the compounds of formula (I) of the present invention, the substituents R ₃ , R ₄ , and R ₅ are assigned as shown below:

Preferably, in the compound of formula (I), the drawing “ --- ” represents a single bond.

Preferably, in the compounds of the invention, including compounds of formula (I), R ₃ is in the para position.

In compounds of the invention, including compounds of formula (I), when R ₃ represents (O) _n C _1-4 alkylene NR ₁₄ R ₁₅ , it is preferably —OC ₂ alkylene NR ₁₄ R ₁₅ (where NR ₁₄ R ₁₅ represents pyrrolidinyl).

According to the present invention there is provided a compound of formula (Ia) below or a salt or derivative thereof:

[Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined above for the compound of formula (I). However, when R ₁ is hydrogen and “ --- ” is a single bond, R ₂ does not represent hydrogen].

The positions of R ₃ , R ₄ and R ₅ shown above for compounds of formula (I) apply equally to compounds of formula (Ia).

The positions of R ₈ and R ₉ shown above for compounds of formula (I) apply equally to compounds of formula (Ia).

In the compounds of formula (Ia), preferably R ₇ represents C _1-6 alkoxy or hydroxy, in particular methoxy or hydroxy.

In the compound of formula (Ia), “ --- ” preferably represents a single bond.

In another preferred embodiment of the invention, there is provided a compound of formula (Ib) below, or a salt or derivative thereof:

[Where:
R ₁ is hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 fluoroalkyl, optionally one or more hydroxy, chloro, bromo Represents C _1-6 alkyl optionally substituted by iodo or NR ₁₀ R ₁₁ group,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as defined above for compounds of formula (I)].

The positions of R ₃ , R ₄ and R ₅ shown above for compounds of formula (I) apply equally to compounds of formula (Ib).

The R ₈ and R ₉ positions indicated above for compounds of formula (I) apply equally to compounds of formula (Ib).

Preferably, in the compound of formula (Ib), R ₁ is hydroxy, C _1-6 alkoxy, C _1-6 fluoroalkyl, optionally by one or more hydroxy, chloro, bromo, iodo or NR ₁₀ R ₁₁ groups. C _1-6 alkyl which may be substituted, especially C _1-6 alkyl, especially methyl.

Preferably, in the compound of formula (Ib), R ₃ may be substituted by hydroxy, C _1-6 alkoxy, or optionally one or more hydroxy, chloro, bromo, iodo or NR ₁₀ R ₁₁ groups. C _1-6 alkyl, especially C _1-6 alkoxy or hydroxy, especially methoxy.

Preferably, in the compound of formula (Ib), R ₃ is in the para position.

Preferably, in the compound of formula (Ib), R ₄ , R ₅ and R ₆ independently represent hydrogen.

Preferably, in the compound of formula (Ib), R ₇ represents hydroxy or C _1-6 alkoxy, in particular hydroxy or methoxy.

Preferably, in the compound of formula (Ib), R ₈ represents hydrogen, hydroxy or C _1-6 alkoxy, especially hydrogen, hydroxy or methoxy, especially hydrogen.

Preferably, in the compound of formula (Ib), R ₈ is in the 3 position.

Preferably R ₉ in the compounds of the formula (Ib) represents hydrogen, hydroxy or C _1-6 alkoxy, especially hydroxy or C _1-6 alkoxy, especially hydroxy or methoxy.

In another embodiment, the present invention provides a compound represented by the following formula (I-bb) or a salt or derivative thereof:

[Wherein R ₁ , R ₃ , R ₄ , R ₇ , R ₈ and R ₉ are as defined above for the compound of formula (Ib)].

In a more preferred embodiment, “ --- ” represents a single bond.

  The preferences given above for the compounds of formula (I-b) apply equally to the compounds of formula (I-bb).

Specific compounds within the scope of this first aspect of the invention are the compounds shown below or salts or derivatives thereof:

Most preferably, the compound of formula (I-bb) is a compound having the structure shown below or a salt or derivative thereof:

In another preferred embodiment, the present invention provides a compound represented by formula (Ic) or a salt or derivative thereof:

[Where:
R ₂ may be substituted by hydroxy, halo, NR ₁₀ R ₁₁ , C _1-3 alkoxy, C _1-3 fluoroalkyl, optionally one or more hydroxy, chloro, bromo, iodo or NR ₁₀ R _{11 Represents a} good C _1-3 alkyl,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as defined above for compounds of formula (I)].

The positions of R ₃ , R ₄ and R ₅ shown above for compounds of formula (I) apply equally to compounds of formula (Ib).

The positions of R ₈ and R ₉ shown above for compounds of formula (I) (R ₉ is in the para position) apply equally to compounds of formula (Ib).

NR ₁₀ R ₁₁ in the compound of formula (Ic) preferably represents hydrogen or C _1-3 alkyl, in particular hydrogen or methyl.

Preferably, in the compound of formula (Ic), R ₂ represents hydroxy, methoxy, methyl or trifluoromethyl.

Preferably, in the compound of formula (Ic), R ₃ is optionally substituted by hydroxy, C _1-6 alkoxy, or optionally one or more hydroxy, chloro, bromo, iodo or NR ₁₀ R ₁₁ groups. C _1-6 alkyl, especially C _1-6 alkoxy such as methoxy, especially methoxy.

Preferably, in the compound of formula (Ic), R ₄ , R ₅ and R ₆ independently represent hydrogen.

Preferably, in the compound of formula (Ic), R ₈ represents hydrogen, hydroxy or C _1-6 alkoxy, more preferably hydrogen or methoxy, especially hydrogen.

Preferably, in the compound of formula (Ic), R ₈ is located at the 3-position.

Preferably, in the compound of formula (Ic), R ₉ represents hydrogen, hydroxy or C _1-6 alkoxy, especially hydroxy or C _1-6 alkoxy, especially hydroxy or methoxy.

More preferably, in the second embodiment, the present invention provides a compound represented by the following formula (I-cc) or a salt or derivative thereof:

[Where:
R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ and R ₉ are as defined above for compounds of formula (Ic)].

  The preferences given above for the compounds of formula (I-c) apply equally to the compounds of formula (I-cc).

Specific compounds of formula (I-cc) are the compounds shown below or salts or derivatives thereof:

  The compounds of formula (I) of the present invention contain two chiral centers. The present invention includes all enantiomers and diastereoisomers, and mixtures thereof in any proportion. The invention also extends to isolated enantiomers or pairs of enantiomers. Methods for separating enantiomers and diastereoisomers are well known to those skilled in the art.

  It will be apparent to those skilled in the art that in the compounds of the present invention, aryl substituents on the heterocycle can be cis or trans relative to each other. Preferably, in the compounds of the invention of formula (I), these substituents can be cis.

  A particularly preferred compound of the present invention is the cis isomer of the compound described as Compound No. 1 above.

  Similarly, particularly preferred compounds are compounds Nos. 2 to 9 in the cis configuration.

  Preferably, the salt of the compound of the present invention is a pharmaceutically acceptable salt.

  The term alkyl is interpreted to include straight and branched chain saturated alkyl groups of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, etc. Is done. More preferably the alkyl group preferably contains 1 to 4 carbon atoms, in particular methyl, ethyl, propyl or isopropyl.

Cycloalkyl includes C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The alkyl or cycloalkyl group is optionally one or more fluorine, chlorine, bromine, iodine, carboxyl, C _1-4 alkoxycarbonyl, C _1-4 alkylamino-carbonyl, di- (C _1-4 alkyl)- It may be substituted by amino-carbonyl, hydroxyl, C _1-4 alkoxy, formyloxy, C _1-4 alkyl-carbonyloxy, C _1-4 alkylthio, C _3-6 cycloalkyl or phenyl.

  Preferably, the alkyl group does not have any substituents.

The term C _1-6 alkoxy includes groups where the alkyl moiety is a straight or branched alkyl moiety. C _1-6 alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and sec-butoxy. Preferably, the C _1-6 alkoxy substituent is methoxy or ethoxy, especially methoxy.

  The term fluoroalkyl includes “alkyl” in which one or more (eg, 1, 2, 3, 4 or 5) hydrogens have been replaced with fluoro. Fluoroalkyl can be a linear or branched “alkyl” unit. Preferred fluoroalkyl groups include trifluoromethyl and pentafluoromethyl.

The term aryl, phenyl, benzyl, be interpreted to include biphenyl and naphthyl, optionally one or more C _1-4 alkyl, hydroxy, C _1-4 alkoxy, carbonyl, C _1-4 alkoxycarbonyl, C _{1- 4} Optionally substituted by alkylcarbonyloxy, nitro or halo.

  The term “halo” is taken to include fluoro, chloro, bromo and iodo, preferably fluoro, chloro.

5- or 6-membered heterocycles and aromatic heterocycles are pyrrole, pyrroline, pyrrolidine, oxazoline, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, furazane, triazole , Thiadiazole, pyridine, piperidine, morpholine, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, thiadiazone and dithiazine, each optionally containing one or more fluorine, chlorine, bromine, iodine, carboxyl, C _{1 -4} alkoxycarbonyl, C _1-4 alkylamino - carbonyl, di - (C _1-4 alkyl) - amino - carbonyl, hydroxyl, C _1-4 alkoxy, formyloxy, C _1-4 alkyl - carbonyl O Shi, optionally substituted by C _1-4 alkylthio or C _3-6 cycloalkyl.

  The compounds of the present invention include all salts (eg, acid addition salts, anionic salts and zwitterionic salts), and particularly include pharmaceutically acceptable salts known to those skilled in the art. The term “pharmaceutically acceptable salt” refers to an organic substance that is charged and can be administered in association with a drug, for example, as a counter-cation or counter-anion of the salt. Or an inorganic component is shown. Pharmaceutically acceptable cations are known to those skilled in the art and include, but are not limited to sodium, potassium, calcium, zinc, and quaternary amines. Pharmaceutically acceptable anions are known to those skilled in the art and include, but are not limited to, chloride, acetate, tosylate, citrate, bicarbonate, and carbonate.

  Pharmaceutically acceptable salts include acetic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, citric acid, cinnamic acid, ethanesulfonic acid, fumaric acid, glutamic acid, glutaric acid, gluconic acid, hydrochloric acid, bromide Hydrogen acid, lactic acid, maleic acid, malic acid, methane sulfonic acid, naphthoic acid, hydroxy naphthoic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, naphthalene acrylic acid, oleic acid, oxalic acid, oxaloacetic acid, phosphoric acid, pyruvic acid, para Including salts derived from toluenesulfonic acid, tartaric acid, trifluoroacetic acid, triphenylacetic acid, tricarballylic acid, salicylic acid, sulfuric acid, sulfamic acid, sulfonic acid and succinic acid.

  The term “pharmaceutically acceptable derivative” or “prodrug” can provide a parent compound or metabolite directly or indirectly when administered to a recipient, or is itself active. Derivatives of active compounds exhibiting, for example, phosphoric acid derivatives and sulfonic acid derivatives Thus, derivatives include solvates, pharmaceutically active esters, prodrugs and the like.

  Preferred compounds of the invention also include all derivatives having a physiologically cleavable leaving group that can be cleaved in vivo to yield a compound of the invention or an active portion thereof. Leaving groups can include acyl groups, phosphoric acid groups, sulfuric acid groups, sulfonic acid groups, preferably mono-, di- and per-acyloxy-substituted compounds (one or more pendant hydroxy groups are acyl groups) , Preferably protected by an acetyl group). In general, acyloxy substituted compounds of the invention can be readily cleaved into the corresponding hydroxy substituted compounds.

  Chemical protection, deprotection of functional groups, synthons (synthetic elements) and other techniques known to those skilled in the art can be used as appropriate to facilitate the synthesis of the compounds of the invention and their starting materials.

  Protection of the functional groups of the compounds and derivatives of the invention is performed by methods well established in the art (for example, as described in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1981). be able to.

  Hydroxyl protecting groups include carboxylic esters (eg acetate), aryl esters (eg benzoate), acetals / ketals (eg acetonide and benzylidene), ethers (eg ortho-benzyl and para-methoxybenzyl ether, Tetrahydropyranyl ether, as well as silyl ethers such as tert-butyldimethylsilyl ether).

  Protecting groups can be removed, for example, by hydrolysis or reduction (eg, hydrogenation) catalyzed by an acid or base. Silyl ethers may require hydrogen fluoride or tetrabutylammonium fluoride for cleavage.

  As will be apparent to those skilled in the art of medicinal chemistry, a compound of formula (I) can be converted to other compounds of formula (I), eg, one or more compounds of formula (I) If it has a hydroxyl substituent, one or more of these substituents can be converted to a halogen (eg, bromo, chloro or iodo) by treating the alcohol with a halogenating agent, in which case the molecule Protecting groups may be used as necessary to protect other functional groups above. Halogenating agents include compounds such as NBS, hydrobromic acid and chlorine gas.

Phenol-type hydroxyls are not easily converted to the corresponding halogen compounds by treatment with a halogenating agent. However, to prepare the desired halogen compound, for example, a suitable arylamine starting material is treated with NaNO ₂ in the presence of HCl under low temperature conditions (such as 0 ° C.) to form the corresponding azide salt. . The azide can then be converted to the desired halo compound by treatment with CuCl, CuBr, KI or HBF ₄ .

A general method for preparing compounds of formula (I) comprises the following steps:
i) Formula (II):

[Where:
R ₁ is hydrogen, hydroxy, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 fluoroalkyl, optionally one or more hydroxy or NR ₁₀ R C _1-6 alkyl _optionally substituted by ₁₁ groups,
R ₆ , R ₇ , R ₈ and R ₉ are independently hydrogen, hydroxy, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 fluoroalkyl, COOR ₁₂ , COR ₁₃ Or represents C _1-6 alkyl optionally substituted by one or more hydroxy or NR ₁₀ R ₁₁ groups]
Or a protected derivative thereof is represented by the formula (III):

[Where:
R ₃ is hydrogen, hydroxy, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 fluoroalkyl, C _2-6 alkenyl, COOR ₁₂ , COR ₁₃ , (O) _n C _1-4 alkylene represents NR ₁₄ R ₁₅ , or C _1-6 alkyl optionally substituted by one or more hydroxy or NR ₁₀ R ₁₁ groups;
R ₄ and R ₅ are independently hydrogen, hydroxy, NR ₁₀ R _11, C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 fluoroalkyl, C _2-6 alkenyl, COOR ₁₂ , COR ₁₃ Or C _1-6 alkyl optionally substituted by one or more hydroxy or NR ₁₀ R ₁₁ groups,
X represents a metal halo moiety]
Treatment with a compound represented by: or a protected derivative thereof;
ii) optionally subsequently converting a tertiary alcohol group on the heterocycle of the product to another substituent;
iii) optionally a deprotecting step thereafter.

  In step i) above, the compound of formula (III) is preferably an organometallic reagent, which is reacted with the ketone compound of formula (II) in an inert atmosphere (eg nitrogen or argon) under anhydrous conditions. In an inert solvent (eg, THF (tetrahydrofuran)) at a non-extreme temperature (eg, room temperature) or low temperature (eg, 0 ° C.).

  Suitable organometallic reagents include organolithium reagents, organomagnesium reagents and organocopper reagents. More preferably, the arylating agent used is an organomagnesium reagent (eg, Grignard reagent), which comprises a compound of formula (III) wherein X represents halo such as bromo and magnesium metal. It can be prepared by reacting in an inert atmosphere under anhydrous conditions.

In step ii) above, the tertiary alcohol substituent on the heterocycle of the product formed by the nucleophilic addition reaction can be changed to other R ₂ substituents by known methods. For example, treatment with para-toluenesulfonic acid can convert the tertiary alcohol group into a convenient leaving group. This intermediate tosylate can then be treated with a nucleophile (eg, hydride source, alcohol or amine) to produce the required substitution in the R ₂ moiety.

  Alternatively, the tertiary hydroxyl can be converted to halogen using a halogenating agent.

In a further embodiment of the invention, the product from the nucleophilic addition reaction is dehydrated to form a compound of general formula (Id) or a protected derivative thereof:

[Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as defined above for the compound of formula (Ib)].

  Dehydration can be facilitated, for example, by catalysis by an acid or base, or by converting a tertiary alcohol to a more convenient leaving group. Preferably the compound of formula (III) is dehydrated by treatment with paratoluenesulfonic acid.

  The preferences expressed above for the compounds of formula (I-b) apply equally to the compounds of formula (I-d).

Specific compounds of formula (Id) are shown below:

  If necessary, double bonds in the heterocycle of the compound of formula (Id) can be removed by treatment with a reducing agent to give other compounds of formula (I). Reducing agents are well known to those skilled in the art and include hydride sources such as borohydrides and alkali metal borohydrides. However, where a suitable catalyst such as palladium on carbon can be used, hydrogen in catalytic hydrogenation is also included. Other suitable hydride sources include sodium triacetoxyborohydride, tetrabutylammonium hydride hydrogenated, and sodium cyanoborohydride.

  Preferably the double bond is reduced by hydrogenation.

The compound of formula (II) is represented by formula (IV):

[Wherein R ₁ , R ₆ , R ₇ , R ₈ and R ₉ are as defined above for the compound of formula (II)]
Can be prepared by reducing the double bond in the heterocycle of the compound represented by or a protected derivative thereof, preferably by hydrogenation.

Compounds of general formula (IV) are prepared by general synthetic methods, as shown in Scheme 1 below and as described in International Application WO 01/17986, the disclosure of which is incorporated herein by reference. Obtainable. This general synthetic method is shown in Scheme 1.

  The compounds used in the preferred synthetic methods of the present invention can be obtained from a number of sources that are readily ascertainable by those skilled in the art. For example, daidzein is readily available or can be synthesized by standard methods known in the art. Suitable methods can be found, for example, in international patent applications WO 98/08503 and WO 00/49009 and references cited therein, which are hereby incorporated by reference in their entirety.

  Obviously, one or more of the above strategies requires the use of one or more protecting groups to protect functionality in other parts of the molecule when performing certain treatments or steps.

  Preferably, any free alcohol, ester or other such reactive group will be protected during the nucleophilic addition reaction, for example as t-butyldimethylsilyl ether.

Chemical modifications and manipulations can be performed on the compounds of the present invention, as will be known to those skilled in the art. For example, an ether derivative with a free phenol group is obtained by the reaction of Compound No. 1 with an alkylating agent. Halogenation of the aromatic ring is also possible, for example by reaction with N-bromosuccinimide, the 8-bromo derivative (compound 42) as the main component is obtained with a small amount of 6-bromo isomer. Further reactions include demethylation of alkoxy groups, which are performed using, for example, hydrogen bromide in acetic acid to give the trihydroxy compound 43.

Additional compounds synthesized by the inventors include the following compounds:

  As used herein, the terms “treatment”, “prevention” or “prevention”, “amelioration” and the like are to be interpreted in the broadest sense. In particular, the term “treatment” does not necessarily imply that an animal is treated until complete recovery. Thus, “treatment” includes improving the sign or severity of a particular symptom, or preventing or otherwise reducing the risk of developing a particular symptom.

  The amount of one or more compounds of the invention required for therapeutic treatment will depend on several factors, including the particular application, the nature of the particular compound used, the condition to be treated, the mode of administration. And patient status.

  The compound of formula (I) can be administered in the manner and amounts conventionally practiced. See, for example, Goodman and Gilman "The pharmacological basis of therapeutics" 7th edition (1985). The specific dosage will depend on the condition to be treated, the condition of the subject, the route of administration and other known factors as indicated above. In general, the daily dose per patient will be in the range of 0.1 mg to 5 g, typically 0.5 mg to 1 g, preferably 50 mg to 200 mg. Depending on the severity of the condition to be treated or alleviated, the length of the dosage may vary from a single dose administered once a day or once every two days to a week to months, optionally several years. It can range from twice or three times daily administration over a period of time.

  Furthermore, for an individual subject, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or directing the administration. It will be understood.

  A relatively short-term treatment with the active compound can be employed to cause cancer stabilization or reduction or remission, and long-term treatment can be employed to prevent the development of cancer in high-risk patients.

  The pharmaceutical compositions for treating the therapeutic indications described herein typically contain the compounds of the present invention (for convenience, hereinafter referred to as “active compounds”) as are well known in the art. Prepared by mixing with one or more pharmaceutically or veterinarily acceptable carriers and / or excipients.

  The carrier must, of course, be acceptable in the sense of being compatible with any other ingredient in the formulation and not deleterious to the subject. The carrier or excipient may be solid, liquid, or both, preferably as a unit dose (e.g. a tablet) that may contain up to 100% by weight of active compound, preferably 0.5-59% by weight of active compound. Formulated with the compound.

  The preferred concentration of the active compound in a drug composition will depend on absorption, distribution, inactivation and excretion rates of the drug, as well as other factors known to those of skill in the art. One or more active compounds can be admixed in the formulations of the invention.

  The formulations of the present invention include oral, rectal, ocular, buccal (eg, sublingual), parenteral (eg, subcutaneous, intramuscular, intradermal or intravenous), transdermal administration (eg, nasal, oral, vaginal, Suitable for inhalation, but in any case the optimal route will depend on the nature and severity of the condition to be treated and the nature of the individual active compounds used. Yes.

  Formulations suitable for oral administration are provided in discrete units, such as capsules, sachets, lozenges or tablets, each containing a predetermined amount of active compound, or as an aqueous or non-aqueous liquid as a powder or granules Or as an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by a suitable method of preparation comprising the step of mixing the active compound with a suitable carrier (which may contain one or more auxiliary ingredients as described above).

  In general, the formulations of the present invention will uniformly and intimately mix the active compound with a liquid or fine solid carrier, or both, and then, if necessary, the resulting mixture so as to form a unit dosage form. It is prepared by molding. For example, a tablet is prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more other ingredients.

  Compressed tablets are made by compressing a free-flowing compound such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant, in a suitable machine. Can be prepared. Molded tablets can be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.

  Formulations suitable for buccal (sublingual) administration include lozenges containing the active compound in a flavored base (usually sucrose and acacia or tragacanth), and inert bases such as gelatin and glycerin or sucrose. And acacia) include lozenges containing this compound.

  Formulations suitable for administration to the eye include solutions, gels and creams containing the active compound in an ophthalmically acceptable carrier or diluent.

  Compositions of the present invention suitable for parenteral administration advantageously comprise a sterile aqueous preparation of the active compound, which preparation is preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration can also take place by subcutaneous, intramuscular or intradermal injection. Such preparations can be conveniently prepared by mixing the compound with water or glycerin buffer, sterilizing the resulting solution and making it isotonic with blood. Injectable preparations according to the invention generally contain from 0.1 to 60% w / v of active compound and may be administered at a rate of 0.1 ml / min / kg.

  Formulations suitable for rectal administration are preferably provided as unit dose suppositories. Formulations suitable for vaginal administration are preferably provided as unit dose pessaries. These can be prepared by mixing the active compound with one or more conventional solid carriers (eg, cocoa butter) and then shaping the resulting mixture.

  Formulations or compositions suitable for topical administration to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Examples of the carrier used include petrolatum, lanolin, polyethylene glycol, alcohol, and combinations of two or more thereof. The active compound is generally present in a concentration of 0.1-5% w / w, especially 0.5-2% w / w. Examples of such compositions include cosmetic skin creams.

  Formulations suitable for transdermal administration may be presented as individual patches configured to remain in intimate contact with the recipient's epidermis for an extended period of time. Such patches preferably contain the active compound as an optionally buffered aqueous solution, for example at a concentration of 0.1-0.2M with respect to the active compound described above. See, for example, Brown, L. et al. (1998).

  Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Panchagnula R et al. (2000)) and are typically buffered, active It takes the form of an aqueous solution of the compound. Suitable formulations include citrate or Bis / Tris buffer (pH 6) or ethanol / water and contain 0.1-0.2M active ingredient.

  Formulations suitable for inhalation can be provided as spray compositions in the form of solutions, suspensions or emulsions. Inhalation spray compositions can further include pharmaceuticals such as hydrogen containing fluorocarbons (eg, 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane). May contain a commercially acceptable propellant.

  The active compound can be provided in the form of a food, for example it can be added to a food, mixed, coated, combined or otherwise added. The term food is used in its broadest sense and includes liquid products such as beverages including dairy products and other foods such as health bars and desserts. Food products containing the compounds of the invention can be readily prepared according to standard methods.

  In a preferred embodiment, the present invention provides a method of treating a human by administering an effective amount of one or more compounds of the present invention or a composition containing the compound.

  The active compound or a pharmaceutically acceptable derivative, prodrug or salt thereof may be combined with other active substances that do not impair the intended action, or substances that supplement the desired action (eg, antibiotics, antifungal agents, It can also be administered in combination with anti-inflammatory drugs or antiviral compounds). The active substance may comprise two or more isoflavones or derivatives thereof as a combination or synergistic mixture. Active compounds also include lipid-lowering agents (eg, probucol, nicotinic acid), platelet aggregation inhibitors (eg, aspirin), antithrombotic agents (eg, coumadin), calcium channel blockers (eg, verapamil, diltiazem, nifedipine), angiotensin It may be administered with a converting enzyme (ACE) inhibitor (eg, captopril, enalapril) and a β-blocker (eg, propanolol, terbutalol, labetalol). The compound may also be administered in combination with a non-steroidal anti-inflammatory drug (eg, ibuprofen, indomethacin, aspirin, fenoprofen, mefenamic acid, flufenamic acid, sulindac) or an antiemetic (eg, Zofran®). Also good. The compound may also be administered with a corticosteroid.

  The compounds of formula (I) may be particularly suitable for co-administration with other anticancer agents such as cisplatin and / or dehydroequol and / or taxol. Administration in combination provides an improved effect on treatment compared to using only one drug.

  This combination administration may be simultaneous or sequential. Simultaneous administration can be accomplished by administering the compounds in the same unit dose or in individual unit doses at or near the same time. Sequential administration may be in any order as required, but typically is in progress of the first or first active agent when the second or subsequent active agent is administered. Physiological effects need to continue, especially when cumulative or synergistic effects are desired.

  The invention also extends to novel intermediates used in the preparation of the compounds according to the invention.

  The compounds of the present invention exhibit abnormal cell survival, abnormal cell proliferation, abnormal cell migration, abnormal angiogenesis, abnormal estrogen / androgen balance, dysfunctional or abnormal steroidogenesis, degenerative changes in the vessel wall. It is useful for the treatment, prevention or amelioration of diseases associated with degeneration, inflammation, and immunological imbalances.

  The invention is further illustrated by the following non-limiting examples and the accompanying drawings.

Example 1
3- (4-Hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-3,4-dihydro-2H-chromen-7-ol
Step 1 : 1- (2,4-Dihydroxy-3-methyl-phenyl) -2- (4-hydroxy-phenyl) -ethanone

2-Methylresorcinol (4.0Og, 1 eq) and 4-hydroxyphenylacetic acid (5.0Og, 1 eq) were added to the round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath and the entire system was placed under nitrogen. To this mixture, distilled BF ₃ .OEt ₂ (20 ml, 5 eq) was added with stirring. The mixture was refluxed (100 ° C.). A yellow solid was produced in 20 minutes indicating that the reaction was complete. The reaction mixture was heated for an additional 10 minutes and then cooled to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200 ml) to remove any excess BF ₃ .OEt ₂ present. ¹ H NMR in d-DMSO shows that the yellow solid is 1- (2,4-dihydroxy-3-methyl-phenyl) -2- (4-hydroxy-phenyl) -ethanone with a purity> 95% It showed that there is. This solid was dried in a freeze dryer for 24 hours (8.93 g, 99%).

Step 2 : 7-Hydroxy-3- (4-hydroxy-phenyl) -8-methyl-chromen-4-one

Add 1- (2,4-dihydroxy-3-methyl-phenyl) -2- (4-hydroxy-phenyl) -ethanone (3.99 g) and N, N-DMF (115 ml) to a two-necked 500 ml round bottom flask The flask was attached to a condenser and placed in an oil bath. An addition funnel was attached to the round bottom flask and the entire system was placed under nitrogen. The flask was heated and maintained at 50 ° C. When BF ₃ .OEt ₂ (57 ml, 29 equivalents) was added dropwise to this solution over 15 minutes, smoke was generated. Methanesulfonyl chloride (MeSO ₂ Cl) (14 ml, 12 eq) was added to the N, N-DMF (14 ml) via a dropping funnel. The mixture was then added dropwise to the round bottom flask over 10 minutes. When the addition was complete, the temperature was raised to the reflux temperature (110 ° C.). The reaction was followed by HPLC (NV06_R & D.m) and was complete in 1 hour 44 minutes. The mixture was cooled to room temperature and poured into chilled distilled water (4 L) with stirring. A clear yellow fluffy precipitate formed immediately and the mixture was left stirring overnight in the cold. The mixture was then filtered through a Buchner funnel to give a yellow solid. ¹ H NMR of this solid in d-DMSO shows that it is 7-hydroxy-3- (4-hydroxy-phenyl) -8-methyl-chromen-4-one and is> 95% pure. Indicated. This solid was dried in a freeze dryer for 24 hours. After drying, the solid was weighed (2.73 g, 66%).

Step 3 : Acetic acid 3- (4-hydroxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester

Hydroxy-3- (4-hydroxy-phenyl) -8-methyl-chromen-4-one (35.18 g) was placed in a round bottom flask (1 L). To this round bottom flask was added pyridine (38 ml, 2 eq) and acetic anhydride (576 ml, 47 eq) with stirring at room temperature. The reaction was followed by HPLC and the reaction was complete immediately. A color change was noted and the reaction mixture was initially dark brown, but after stirring, it became a bright orange color with tan cotton-like particles. The reaction mixture was poured into cold distilled water (4 L) and allowed to stir at room temperature for 30 minutes. An off-white solid was collected by suction filtration. ¹ H NMR of this solid in d-CDCl ₃ shows that it is acetic acid 3- (4-hydroxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester, purity> 95 %. This solid was dried in a freeze dryer for 24 hours. After drying, the solid was weighed (31.80 g, 69%).

Step 4 : Acetic acid 3- (4-hydroxy-phenyl) -8-methyl-4-oxo-chroman-7-yl ester

Acetic acid 3- (4-hydroxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester (26.32 g), 10% Pd / Al ₂ O ₃ (12.93 g, 50%), and acetic acid Ethyl (EtOAc) (1.5 L) was added into a hydrogenation round bottom flask (2 L). The flask was placed on a hydrogenator, evacuated, and purged with nitrogen gas (x5) and hydrogen gas (x5). The reaction was followed by HPLC. 10% Pd / Al ₂ O ₃ (9 g, 35%) was added to the round bottom flask over 40 hours, but no product peak was present, indicating only the starting material was present. HPLC at 62 hours showed that the main peak was the product peak (the starting material peak is half the height of the product peak). To speed up the reaction, 10% Pd / Al ₂ O ₃ (5.69 g, 20%) was added to the round bottom flask. The reaction was complete in 64 hours. The reaction mixture was filtered through celite to remove the Pd / Al ₂ O ₃ catalyst and the celite was washed with EtOAc (1 L) to ensure that most of the product was recovered. EtOAc was evaporated on a rotary evaporator to give a yellow solid. This solid was recrystallized in 95% EtOH (650 ml) and placed in a freezer overnight. Off-white crystals were collected by suction filtration. ¹ H NMR in d-CDCl ₃ shows that the off-white crystals are acetic acid 3- (4-hydroxy-phenyl) -8-methyl-4-oxo-chroman-7-yl ester, purity> 95% Showed that. The crystals were stored in a desiccator for 24 hours and weighed (18.37 g, 69%).

Step 5 : 7-Hydroxy-3- (4-hydroxy-phenyl) -8-methyl-chroman-4-one

Acetic acid 3- (4-hydroxy-phenyl) -8-methyl-4-oxo-chroman-7-yl ester (18.37g), imidazole (21.18g, 6eq), and 100% EtOH (536ml) in a round bottom flask To (2 L). The reaction mixture was refluxed and followed by HPLC. The reaction was complete in 8 hours. The reaction mixture was concentrated on a rotary evaporator (about 130 ml) and poured into cold distilled water (1.9 L) with stirring. The water crash out was left in place while stirring in the cold overnight. A pale pink solid was collected by suction filtration. ¹ H NMR of this solid showed it to be 7-hydroxy-3- (4-hydroxy-phenyl) -8-methyl-chroman-4-one with a purity> 95%. This solid was dried in a freeze dryer for 3 hours (8.31 g, 59%).

Step 6 : 7,4'-bis tert-butyldimethylsilyloxy-8-methyl-dihydrodaidzein

  8-methyldihydrodaidzein 4.2 g, imidazole 13 g, tert-butyldimethylsilyl chloride 12.7 g (70 mmoles), and N, N-DMF 50 ml were combined in a 250 ml round bottom flask and stirred at room temperature under nitrogen for 16 hours. . Cold water (100 ml) was added to quench the reaction and the reaction mixture was cooled in an ice bath. The white solid was collected by filtration and washed with water. Recrystallization from ethanol gave 3.2 g of white fluffy crystals.

Step 7 : 7- (tert-butyldimethylsilyloxy) -3-3- (4- (tert-butyldimethylsilyloxy) phenyl) -4- (4-methoxyphenyl) -8-methyl-3,4-dihydro -2H-chromen-4-ol

2.5 g of the product from step 6 was weighed in a two neck round bottom flask and flushed under nitrogen. 10 ml of anhydrous THF was added to the reaction vessel to obtain a slightly yellow clear solution. A condenser was attached and the reaction vessel was placed in an ice bath. 22.5 ml of commercial 4-methoxyphenylmagnesium bromide (0.5M solution in THF) was added dropwise to the reaction mixture over 10 minutes. Aqueous ether (H ₂ O: diethyl ether 50:50) was added dropwise to stop the reaction, but this time also under nitrogen. A white precipitate formed as the amount of water added increased. An additional amount of water was added to the reaction mixture and then extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to give a clear yellow oil. This was allowed to solidify overnight to give an off-white solid. Due to the greasy nature of this material, an accurate yield could not be calculated. The product was not further purified before use in the next reaction. Due to the greasy nature of this material, an accurate yield could not be calculated.

Process 8 : 3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -2H-chromen-7-ol

  4.2 g of the product of Step 7, 4.5 g of pTsOH (p-toluenesulfonic acid), boiling tip, and 200 ml of ethanol were combined in a two-necked 500 ml round bottom flask equipped with a condenser. The reaction mixture was heated to reflux for 3 hours. The solvent was concentrated under vacuum to about 20 ml and then poured into cold water (100 ml) with stirring. The mixture is then extracted with ethyl acetate and the organic layers are combined, washed with water (3 x 100 ml) and brine (1 x 100 ml), dried over anhydrous magnesium sulfate and filtered, and the solvent removed in vacuo. A reddish brown oil was obtained. This oil was dissolved in methanol (about 15 ml) and placed in a freezer overnight. A white precipitate was formed overnight and was collected by filtration and washed with methanol. The filtrate was concentrated in vacuo to give a brown oil.

Step 9 : 3- (4-Hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-3,4-dihydro-2H-chromen-7-ol

2.5 g of the product of Step 8, 0.4 g of 10% Pd / Al ₂ O ₃ and 50 ml of ethanol were combined in a two neck 100 ml round bottom flask. The reaction mixture was hydrogenated under standard conditions at low pressure for 3 hours. The reaction mixture was filtered through Celite to remove the catalyst, and washed with ethanol (100 ml). The filtrate was concentrated to about 15 ml and then poured into cold water (300 mL) with stirring. A pale orange precipitate was formed, which later formed a brown oil. The mixture was then extracted with diethyl ether and the organic layers were combined, washed with water (3 × 100 ml) and brine (1 × 100 ml), dried over anhydrous magnesium sulfate and filtered. Removal of the solvent in vacuo gave a reddish brown oil. The product was recrystallized from diethyl ether (ca. 15 ml) to give a brown solid which was washed with cold diethyl ether to give off-white crystals. The four yields of (IV) were about 1 g. ^{The 1} H NMR spectrum and numbering method are shown below.

Example 2
3- (4-Hydroxyphenyl) -4- (4-methoxyphenyl) -3 ', 4'-dimethoxy-8-methyl-3,4-dihydro-2H-chromen-7-ol
Step 1.1 : 1- (2,4-Dihydroxy-3-methyl-phenyl) -2- (3,4-dimethoxy-phenyl) ethanone

2-Methylresorcinol (6.285 g, 1 eq) and 3,4-dimethoxyphenylacetic acid (9.251 g, 1 eq) were added to the round bottom flask. The round bottom flask was attached to a condenser and placed in an oil bath, and the entire system was kept under nitrogen. Distilled boron trifluoride diethyl etherate BF ₃ .OEt ₂ (42 ml, 5 eq) was added to the mixture with stirring. The mixture was refluxed (110 ° C.). A yellow solid was formed in 75 minutes indicating that the reaction was complete. The reaction mixture was heated for an additional 10 minutes and then allowed to cool to room temperature. The yellow solid was collected by suction filtration and washed with distilled water (200 ml) to remove any excess BF ₃ .OEt ₂ present. ¹ H NMR in d-DMSO shows that the yellow solid is 1- (2,4-dihydroxy-3-methyl-phenyl) -2- (3,4-dimethoxy-phenyl) ethanone and purity> 95 %. This solid was dried in a freeze dryer for 24 hours (6.303 g, 43%).

Step 2.1 : 3- (3,4-Dimethoxy-phenyl) -7-hydroxy-8-methyl-chromen-4-one

1- (2,4-Dihydroxy-3-methyl-phenyl) -2- (3,4-dimethoxy-phenyl) ethanone (1078-1-49; 9.999 g, 34.4 mmol) in N, N-DMF (15 mL ) And dried over MgSO ₄ . Distilled BF ₃ -OEt ₂ (16.08.04) was added dropwise at room temperature under N ₂ atmosphere. Heating was started after 20 minutes. After 1 hour, methanesulfonyl chloride in DMF (8 mL in 20 mL) was added slowly at 50 ° C. The reaction mixture was heated to reflux for 1.5 hours. This opaque yellow solution was added to 1.2 L of vigorously stirred cold water and left at 4 ° C. overnight. An opaque yellow solid was collected by filtration and placed in water to remove residual BF ₃ -OEt ₂ . The solid was collected by filtration and dried overnight using a lyophilizer. ¹ H NMR in d-DMSO shows the yellow solid is 3- (3,4-dimethoxy-phenyl) -7-hydroxy-8-methyl-chromen-4-one and 90% pure. (8.85 g, 82%).

Step 3.1 : Acetic acid 3- (3,4-dimethoxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester

3- (3,4-Dimethoxy-phenyl) -7-hydroxy-8-methyl-chromen-4-one (9.82 g, 31 mmol), acetic anhydride (62 ml), and pyridine (6.2 ml) in a round bottom flask Combined and heated to reflux. After heating for 3 hours, the reaction mixture was cooled to room temperature, producing a crystalline solid. The solid was filtered and washed with H ₂ O (1 L). ¹ H NMR on d-CDCl ₃ shows that the light brown crystals are acetic acid 3- (3,4-dimethoxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester, purity 90 % (7.214 g, 71%).

Step 4.1 : Acetic acid 3- (3,4-dimethoxy-phenyl) -8-methyl-4-oxo-chroman-7-yl ester

3- (3,4-Dimethoxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester (1.12 g, 3 mmol), 10% Pd / Al ₂ O ₃ (0.501 g, 45% w / w), and dry EtOAc (100 ml) were placed in a two-necked round bottom flask and placed on a hydrogenator. After 4 hours, one main product was observed. The reaction mixture was purged and the catalyst was filtered through celite. The filtrate was concentrated to give a white solid. ¹ H NMR on d-CDCl ₃ shows that this solid is acetic acid 3- (3,4-dimethoxy-phenyl) -8-methyl-4-oxo-chroman-7-yl ester and is 85% pure. (1.1 g).

Step 5.1 : 3- (3,4-Dimethoxy-phenyl) -7-hydroxy-8-methyl-chroman-4-one

Acetic acid 3- (3,4-dimethoxy-phenyl) -8-methyl-4-oxo-chroman-7-yl ester (1.1 g, 3.2 mmol) and imidazole (3.2 g, 47 mmol) were refluxed in EtOH (100 ml). I let you. The reaction was complete after 90 minutes, allowed to cool to room temperature and then poured into stirred H ₂ O (800 ml). A fine white precipitate was collected by filtration. ¹ H NMR with d-CDCl ₃ shows that the solid is 3- (3,4-dimethoxy-phenyl) -7-hydroxy-8-methyl-chroman-4-one and is> 95% pure. Indicated (0.31 g, 30%).

Step 6.1 : 7,4'-bis tert-butyldimethylsilyloxy-3 ', 4'-dimethoxy-8-methyl-dihydrodaidzein

  2 g of 3 ', 4'-dimethoxy-8-methyldihydrodaidzein, 6.8 g of imidazole, 6.3 g of tert-butyldimethylsilyl chloride, and 50 ml of N, N-DMF were combined in a 250 ml round bottom flask and allowed to come under nitrogen at room temperature for 16 Stir for hours. The reaction was quenched by the addition of cold water (100 ml) and the reaction mixture was cooled with an ice bath. The white solid was collected by filtration and washed with water. Recrystallization from ethanol gave 2.2 g of white fluffy crystals.

Step 7.1 : 7- (tert-butyldimethylsilyloxy) -3-3- (4- (tert-butyldimethylsilyloxy) phenyl) -4- (4-methoxyphenyl) -3 ', 4'-dimethoxy-8- Methyl-3,4-dihydro-2H-chromen-4-ol

2 g of the product from step 6.1 above was weighed in a two neck round bottom flask and flushed under nitrogen. 10 ml of anhydrous THF was added to the reaction vessel to obtain a slightly yellow clear solution. A condenser was attached and the reaction vessel was placed in an ice bath. 22.5 ml of commercial 4-methoxyphenylmagnesium bromide (0.5M solution in THF) was added dropwise to the reaction mixture over 10 minutes. Aqueous ether (H ₂ O: diethyl ether 50:50) was added dropwise to stop the reaction, but this time also under nitrogen. A white precipitate formed as the amount of water added increased. An additional amount of water was added to the reaction mixture and then extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to give a clear yellow oil. This was allowed to solidify overnight to give an off-white solid. Due to the greasy nature of this material, an accurate yield could not be calculated. The product was not further purified before use in the next reaction. Due to the greasy nature of this material, an accurate yield could not be calculated.

Step 8.1 : 3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -3 ', 4'-dimethoxy-8-methyl-2H-chromen-7-ol

  2 g of product from step 7.1, 4.5 g of pTsOH, boiling tip, and 100 ml of ethanol were combined in a two neck 500 ml round bottom flask fitted with a condenser. The reaction mixture was heated to reflux for 3 hours. The solvent was concentrated under vacuum to about 10 ml and then poured into cold water (100 ml) with stirring. The mixture is then extracted with ethyl acetate and the organic layers are combined, washed with water (3 x 100 ml) and brine (1 x 100 ml), dried over anhydrous magnesium sulfate and filtered, and the solvent removed in vacuo. A reddish brown oil was obtained. This oil was dissolved in methanol (about 15 ml) and placed in a freezer overnight. A white precipitate was formed overnight and was collected by filtration and washed with methanol. The filtrate was concentrated in vacuo to give a brown oil that crashed out into water to give a light brown solid.

Step 9.1 : 3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -3 ', 4'-dimethoxy-8-methyl-3,4-dihydro-2H-chromen-7-ol

1 g of the product of step 8.1, 0.2 g of 10% Pd / Al ₂ O ₃ and 25 ml of ethanol were combined in a two neck 100 ml round bottom flask. The reaction mixture was hydrogenated under standard conditions at low pressure for 3 hours. The reaction mixture was filtered through Celite to remove the catalyst, and washed with ethanol (100 ml). The filtrate was concentrated to approximately 5 ml and then poured into cold water (100 mL) with stirring. A pale orange precipitate was formed, which later formed a brown oil. The mixture was then extracted with diethyl ether and the organic layers were combined, washed with water (3 × 100 ml) and brine (1 × 100 ml), dried over anhydrous magnesium sulfate and filtered. Removal of the solvent in vacuo gave a reddish brown oil. The product was recrystallized from diethyl ether (ca. 5 ml) to give a brown solid which was washed with cold diethyl ether to give off-white crystals. The four yields of (IV) were about 0.2 g. ^{The 1} H NMR spectrum and numbering method are shown below.

¹ H NMR assignment results in the following compounds:

2.0. Materials and Methods
2.1. Tissue culture human pancreatic cancer cell line HPAC (CRL-2119) was transformed into HEPES (15 mM), insulin (0.002 mg / ml), transferrin (0.005 mg / ml), hydrocortisone (40 ng / ml), epidermal growth factor The cells were cultured in a conventional manner in a 1: 1 mixed medium of DMEM (Sigma) and Ham's F12 (Sigma) containing (10 ng / ml). CP70, an ovarian cancer cell line, was given by Dr. Gil Mor (Yale University), cultured in a 1: 1 mixed medium of DMEM and Ham's F12, and SKOV-3 was purchased from ATCC, McCoys 5a medium In culture. The breast cancer cell line MDA-MB-468 was cultured in Leibovitz's L-15 medium. The melanoma cell line MM200 was a gift from Dr. Peter Hersey (University of Newcastle) and A2058 was a gift from Dr. Peter Parsons (QIMR). Both were cultured in DMEM medium.

All cultures are supplemented with 10% FCS (CSL, Australia), penicillin (100 U / ml), streptomycin (100 mg / ml), L-glutamine (2 mM) and sodium bicarbonate (1.2 g / L), 5% The cells were cultured at 37 ° C. in a humidified atmosphere of CO ₂ . Except where noted, all cell lines were purchased from ATCC (Maryland, USA).

The normal cell line, NFF (neonatal foreskin fibroblasts), was a gift from Dr. Peter Parsons (Queensland Institute of Medical Research). RK (rabbit kidney) cells were a gift from Dr. Miller Whalley (Macquarie University). Both cell lines were run in RPMI medium supplemented with 10% FCS (CSL, Australia), penicillin (100 U / ml), streptomycin (100 mg / ml), L-glutamine (2 mM) and sodium bicarbonate (1.2 g / L). The cells were cultured at 37 ° C. in a humidified atmosphere of 5% CO ₂ .

2.2. Proliferation assay IC50 values were determined for each cell line. Cells were plated in 96-well plates at the appropriate cell density (determined from growth rate analysis) and cultured for 5 days with or without the test compound. Cell growth was performed with 20 μl of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT, 2.5 mg / ml in PBS, Sigma) at 37 ° C according to the manufacturer's instructions. Evaluation was made after 3-4 hours of addition. IC50 values were calculated from a semi-log plot of% versus control growth on the y-axis versus log dose on the x-axis.

2.3. Pharmacokinetics of Compound No. 1- Oral Compound No. 1 above was prepared as a homogeneous suspension in 1% CMC (m: v, water). This formulation was orally administered to female BALB / c mice at a dose of 50 mg / kg by gavage. Three animals were assigned to each time point (15 minutes, 30 minutes, 1 hour, 4 hours, 24 hours). At each time point, animals were euthanized by cervical dislocation and blood was collected. The concentration of free compound was analyzed by mass spectrometry.

3.0. Results
3.1. Toxicity to normal cells Two replicate assays of cytotoxicity to rabbit kidney cells demonstrated that compound No. 1 was weakly toxic to these cells (Table 1). When compared to cisplatin and phenoxodiol (another benchmark that can test anticancer drug candidates), Compound No. 1 showed a higher degree of toxicity than both comparative compounds (Compound No. 1 was 2 μM) In contrast, cisplatin is 9.9 μM).

3.2. In vitro efficacy against cancer cells When comparing IC50 values of phenoxodiol and compound No. 1, compound No. 1 is ovarian cancer cell line (CP70), AR negative p53 Mt prostate cancer cell line (PC3), Excellent activity (2-10 fold increase) against ER negative (p53 mt) breast cancer cell lines (MDA-MB-468, respectively), p53 Mt glioma (HTB-138), and p53 Mt small cell lung cancer Shown (Table 2). Compound No. 1 showed anti-cancer activity comparable to phenoxodiol against all other cell lines tested except for the colorectal cell line HT-29 (Table 2). Compound No. 1 was also equally effective against melanoma cell line MM200 (Table 2.1).

Therefore, Compound No. 1 shows good anticancer activity against a wide variety of cancer cells including ovarian cancer, prostate cancer, breast cancer, glioma, pancreatic cancer, lung cancer, colorectal cancer, melanoma .

Many cancer cell lines were used to test analogs of Compound No. 1 and compare their IC50 values. The results show that Compound No. 1 is the best for a wide range of cell lines, but Compound No. 20 also showed good results for ovarian cancer, prostate cancer, breast cancer, leukemia and melanoma cell lines. . Compounds No. 15 and No. 17 also showed good results against the ovarian cancer cell line and melanoma cell line, respectively (Table 2.2).

3.3. Pharmacokinetics of Compound No. 1-Oral oral pharmacokinetics were investigated in female BALB / c mice. 15 minutes after administration, 27.3 μM Cmax of free compound No. 1 was observed in the serum. Compound No. 1 rapidly disappeared from the serum, and a concentration of 8.2 μM was observed after 30 minutes and 2.4 μM after 1 hour. As a result, the half-life of this drug is about 30 minutes (Figure 1 and Table 3). The majority of Compound No. 1 in serum is present in its conjugated state, and the concentration of Compound No. 1 as a whole (free + conjugated) reached about 100 μM 15 minutes after administration (free: total 1: 4 ). The free: overall ratio decreased over time (1:12 after 30 minutes, 1:13 after 1 hour). The rapid appearance of Compound No. 1 at a high concentration (815 μM) in urine 15 minutes after administration is evidence that Compound No. 1 is absorbed from the gastrointestinal tract and excreted through the kidney.

The concentration of Compound No. 1 in urine peaked at 30 minutes (2640 μM) and decreased to levels of about 1500 μM and 545 μM at 1 hour and 4 hours after administration, respectively. The majority of this compound was present in its conjugated form, and it was observed that less than 2% of the free compound was observed at any time. A high proportion of this compound was also excreted in the feces, which was observed at least 1 hour after administration. However, it was not possible to confirm whether hepatic excretion is the mode of removal of this compound. This is because none of the liver samples were evaluated, and the presence of this compound in the stool may be due to residual powder of the compound not absorbed from the gastrointestinal tract. It is interesting to note that almost 100% of the compounds recovered from stool were present in their free form.

Comparing the oral pharmacokinetic data of phenoxodiol and compound No. 1 shows that they have similar half-lives, but 10-20 times higher concentrations of free compound No. 1 were achieved after 15 and 30 minutes. It was. A concentration twice as high was observed after 1 hour.

4.0. Effect on LPS-stimulated mouse macrophages (RAW 264.7) The mouse macrophage cell line RAW 264.7 was cultured in DMEM supplemented with fetal calf serum (FCS), 2 mM glutamine and 50 U / ml penicillin / streptomycin. Sub-confluent cells were gently scraped from the flask, seeded at 5 × 10 ⁵ cells / well in a 24-well plate and allowed to adhere for 1 hour. Cells were then treated with either a test compound at a concentration of 10 μM (in 0.025% DMSO) or vehicle alone and incubated for 1 hour. LPS 50 ng / ml (LPS-Sigma-Aldrich) was then added. After 16 hours of incubation, the media was collected and stored at −80 ° C. for ecosanoid measurements using enzyme immunoassays (PGE ₂ and TXB ₂ -Cayman Chemical).

CONCLUSION Compound No. 1 is significantly less concentrated than cisplatin on primary explants of untransformed neonatal foreskin fibroblasts (IC50 = 2 μM for compound No. 1 vs 9 μM for cisplatin) Of toxicity. However, relatively mild toxicity was observed for rabbit kidney cells (Compound No. 1 IC50> 60 μM). Effectiveness studies have demonstrated that compound No. 1 is effective against cell lines representing melanoma (MM200) and glioma (HTB-128). However, this compound is effective against cell lines representing prostate cancer (PC3), breast cancer (MDA-MB-468) and lung cancer (NCIHH-H23), which have been considered to be very difficult to treat. It seems to be particularly effective.

  Compound No. 1 showed a moderate effect on colorectal cell line HT-29.

  Pharmacokinetic analysis of Compound No. 1 reveals that oral administration of this drug results in significantly higher free concentrations of this drug at 15 and 30 minutes after administration than similarly administered phenoxodiol Became. Compound No. 1 and phenoxodiol each show a similar t1 / 2 (about 30 minutes).

  Preliminary formulation experiments with Compound No. 1 show that this molecule has moderate to low solubility in 20% HPBCD (11.2 mg / ml).

  The present invention has been described herein with reference to certain preferred embodiments so that the present invention can be practiced without undue experimentation. However, one skilled in the art will readily appreciate that many of the components and parameters can be altered or modified to some extent without departing from the scope of the present invention. Furthermore, titles, headings, etc. are given to enhance the reader's understanding of the specification and should not be construed as limiting the scope of the invention.

  The entire disclosure of all applications, patents and publications cited herein are hereby incorporated by reference.

  Throughout the specification and claims, unless otherwise indicated, the term “comprising” and variations such as “comprising” are meant to encompass the specified integer or step or group of integers or steps. It will be understood that other integers or steps or groups of integers or steps are not excluded.

  Those skilled in the art will recognize that the invention described herein is susceptible to variations and modifications other than those specifically described. The present invention should be understood to include all such changes and modifications. The present invention also encompasses all of the steps, features, compositions and compounds described or shown individually or collectively herein, and any and any two or more of the steps or features. Includes all combinations.

  References to prior art herein are not an admission that the prior art forms part of the common general knowledge in the field of Endeavor, nor is it an indication of any form, and such admission Or should not be interpreted as a suggestion.

Selected references
Constantinou AI, Mehta R, Husband A. 2003 Phenoxodiol, a novel isoflavone derivative, inhibits dimethylbenz [a] anthracene (DMBA) -induced mammary carcinogenesis in female Sprague-Dawley rats (a novel isoflavone derivative phenoxodiol is a female Sprague- Suppresses dimethylbenz [a] anthracene-induced breast cancer development in Dawley rats) Eur J Cancer. 39, 1012-8.
Constantinou AI, Husband A. 2002 Phenoxodiol (2H-1-benzopyran-7-0,1,3- (4-hydroxyphenyl)), a novel isoflavone derivative, inhibits DNA topoisomerase II by stabilizing the cleavable complex (a novel isoflavone derivative) Certain phenoxodiols (2H-1-benzopyran-7-0,1,3- (4-hydroxyphenyl)) inhibit DNA topoisomerase II by stabilizing the cleavable complex) Anticancer Res. 22, 2581-5.
Gamble, JR., Xia, P., Hahn, C., Drew, J., Drogemuller, C., Carter, C., Walker, C., Brown, DM., Vadas, MA. 2003 Phenoxodiol, a derivative of plant flavanoids, shows potent anti-tumour and anti-angiogenic properties (Fenoxodiol, a derivative of plant flavonoids, exhibits potent anti-tumor and anti-angiogenic effects) Nature Medicine.
Hersey, P and Zhang, XD 2001 How melanoma cells evade Trail-induced apoptosis (Nature reviews, Cancer, 1, 142-150.
Kamsteeg, M., Rutherford, T., Sapi, E., Hanczaruk, B., Shahabi, S., Flick, M., Brown, DM and Mor, G. 2003 Phenoxodiol-an isoflavone analogue- induces apoptosis in chemo- resistant ovarian cancer cells (phenoxodiol-isoflavone analog-induces apoptosis in chemoresistant ovarian cancer cells) Oncogene, 22, 2611-20.

2 shows the pharmacokinetics and distribution of Compound No. 1 in serum, stool and urine. Mean values (± SEM) for the free and total concentrations of this compound are expressed as a semi-log plot in Part A and as a standard linear plot in Part B.

Claims (25)

General formula (Ia):

[Where:
R ₁ is hydrogen, hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 fluoroalkyl, or C _1-6 alkyl,
Drawing "---" and R _2, either together represent a double bond, or drawing "---" represents a single bond, R ₂ is hydrogen or hydroxy,
R ₃ is hydroxy, C _{1 -} a ₆ alkyl, _{- 6} alkoxy or C _1,
R _4, R ₅ , R ₆ , R ₈ and R ₉ are independently hydrogen, hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _1-6 fluoroalkyl, C _2-6 alkenyl, COOR ₁₂ , COR ₁₃ , or C _1-6 alkyl;
R ₇ is hydroxy,
R ₁₀ , R ₁₁ and R ₁₂ are independently hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or trialkylsilyl;
R ₁₃ is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl or NR ₁₀ R ₁₁ ,
(However, when R ₁ represents hydrogen and “ --- ” is a single bond, R ₂ is not hydrogen)]
Or a pharmaceutically acceptable salt thereof. Formula (Ib):

[Where:
R ₁ represents hydroxy, halo, NR ₁₀ R ₁₁ , C _3-6 cycloalkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 fluoroalkyl, or C _1-6 alkyl,
R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined in claim 1 ]
The compound of Claim 1 which is a compound represented by these.   R _Three 3. A compound according to claim 1 or 2 wherein is in the para position.   R _Four , R _Five , And R ₆ The compound according to any one of claims 1 to 3, wherein is hydrogen.   R ₈ And R ₉ Is independently hydrogen, hydroxy, or C _{1 − 6} The compound according to any one of claims 1 to 4, which is alkoxy.   The compound according to any one of claims 1 to 5, wherein the drawing "---" represents a single bond. Formula (I-bb):

[Wherein R ₁ , R ₃ , R ₄ , R ₇ , R ₈ and R ₉ are as defined in claim 2 ]
The compound of Claim 2 which is a compound represented by these, or its pharmaceutically acceptable salt . The following compound numbers 1, 3, 4, 6, 8, 9 and 42, namely:
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-7-ol (Compound No. 1),
3- (3,4-dimethoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-7-ol (Compound No. 3),
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-7-ol (Compound No. 4),
3- (3-methoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-7-ol (Compound No. 6),
3- (3-hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-7-ol (Compound No. 8),
3- (3,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-7-ol (Compound No. 9),
3- (4-Hydroxyphenyl) -4- (4-methoxyphenyl) -8-bromo-chroman-7-ol (Compound No. 42)
The compound according to claim 7 or a pharmaceutically acceptable salt thereof selected from: Compound No. 1.1 and Compound No. 3.1 shown below

9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, selected from: Formula (Ic):

[Where:
R ₂ represents hydroxy ,
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , and R ₉ are as defined in claim 1]
The compound of Claim 1 which is a compound represented by these, or its pharmaceutically acceptable salt . Formula (I-cc):

[Wherein R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ , and R ₉ are as defined in claim 10]
11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, which is a compound represented by: The following compound numbers 10, 11, 14-16, 18, 19, 21 and 23-25, ie
3- (4-hydroxyphenyl) -4- (4-methylphenyl) -chroman-4,7-diol (Compound No. 10),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -chroman-4,7-diol (Compound No. 11),
3- (4-hydroxyphenyl) -4-phenyl-chroman-4,7-diol (Compound No. 14),
3- (4-hydroxyphenyl) -4- (3-methoxyphenyl) -chroman-4,7-diol (Compound No. 15),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-4,7-diol (Compound No. 16),
3- (3,4-dimethoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-4,7-diol (Compound No. 18),
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-4,7-diol (Compound No. 19),
3- (3-methoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-4,7-diol (Compound No. 21),
3- (3-hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-4,7-diol (Compound No. 23),
3- (3,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-chroman-4,7-diol (Compound No. 24),
3- (4-hydroxyphenyl) -4- (3-aminophenyl) -chroman-4,7-diol (Compound No. 25),
12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof selected from Formula (Id):

[Wherein R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as defined in claim 1]
The compound of Claim 1 which is a compound represented by these, or its pharmaceutically acceptable salt . The following compound numbers 26 , 27, 30-32, 34, 35, 37, 39-41 and 44, i.e.
3- (4-hydroxyphenyl) -4- (4-methylphenyl) -2H-chromen-7-ol (Compound No. 26),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -2H-chromen-7-ol (Compound No. 27),
3- (4-hydroxyphenyl) -4-phenyl-2H-chromen-7-ol (Compound No. 30),
3- (4-hydroxyphenyl) -4- (3-methoxyphenyl) -2H-chromen-7-ol (Compound No. 31),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-2H-chromen-7-ol (Compound No. 32),
3- (3,4-dimethoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-2H-chromen-7-ol (Compound No. 34),
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-2H-chromen-7-ol (Compound No. 35),
3- (3-methoxyphenyl) -4- (4-methoxyphenyl) -8-methyl-2H-chromen-7-ol (Compound No. 37),
3- (3-hydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-2H-chromen-7-ol (Compound No. 39),
3- (3,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -8-methyl-2H-chromen-7-ol (Compound No. 40),
3- (4-hydroxyphenyl) -4- (3-aminophenyl) -2H-chromen-7-ol (Compound No. 41),
3- (3,4-Dimethoxyphenyl) -4- (4-methoxyphenyl) -2H-chromen-7-ol (Compound No. 44)
14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof selected from The following compound numbers 2, 5, 7, 12, 13, 17, 20, 22, 29, 33, 36, 38 and 45, ie
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-chroman (Compound No. 2),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-chroman (Compound No. 5),
3- (3,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-chroman (Compound No. 7),
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-chroman-4-ol (Compound No. 12),
3- (4-methoxyphenyl) -4- (3-methoxyphenyl) -7-methoxy-chroman-4-ol (Compound No. 13),
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-chroman-4-ol (Compound No. 17),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-chroman-4-ol (Compound No. 20),
3- (3,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-chroman-4-ol (Compound No. 22),
3- (4-methoxyphenyl) -4- (3-methoxyphenyl) -7-methoxy-2H-chromene (Compound No. 29),
3- (4-methoxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-2H-chromene (Compound No. 33),
3- (4-hydroxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-2H-chromene (Compound No. 36),
3- (3,4-dihydroxyphenyl) -4- (4-methoxyphenyl) -7-methoxy-8-methyl-2H-chromene (Compound No. 38),
3- (4-Hydroxyphenyl) -4- (4-phenoxyphenyl) -2H-chromen-7-ol (Compound No. 45)
Or a pharmaceutically acceptable salt thereof. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for chemotherapy, or a medicament for use as a radiosensitizer or a chemosensitizer. . Use according to claim 16 , wherein the medicament used as chemotherapy or radiosensitizer or chemosensitizer is for the treatment of cancer or tumor mass. Wherein the cancer or tumor mass epithelial, mesenchymal origin, or derived from nerves, use according to claim 17. The cancer is prostate cancer, ovarian cancer, cervical cancer, breast cancer, gallbladder cancer, pancreatic cancer, colorectal cancer, kidney cancer, non-small cell lung cancer, melanoma, mesothelioma, sarcoma cancer cell or glioma Use as described in 18. 17. Use according to claim 16, wherein the compound is a chemotherapy sensitizer for cisplatin, dehydroequol or taxol.   Use according to claim 16, wherein the chemotherapy sensitizer is for the treatment of ovarian cancer or pancreatic cancer. A method for producing a pharmaceutical composition comprising the step of contacting the compound according to any one of claims 1 to 15 with a pharmaceutically acceptable carrier or diluent. 16. One or more compounds according to any one of claims 1 to 15 or pharmaceutically acceptable salts thereof together with one or more pharmaceutical carriers, excipients, adjuvants and / or diluents A pharmaceutical composition containing. 24. The pharmaceutical composition of claim 23 , further comprising another chemotherapeutic agent. 25. A pharmaceutical composition according to claim 24, wherein the another chemotherapeutic agent is cisplatin, dehydroequol or taxol.

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