KR20070060091A - Arene ruthenium (ii) compounds and their use in cancer therapy - Google Patents

Abstract

or a solvate or prodrug thereof, wherein: R1, R1, R3, R4, R5 and R6 are independently selected from H, C1-7 alkyl, C5-20 aryl, C3-20 heterocyclyl, halo, ester, amido, acyl, sulfo, sulfonamido, ether, thioether, azo, amino, or R1 and R2 together with the ring to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group containing up to three 3- to 8- membered carbocyclic or heterocyclic rings, wherein each carbocyclic or heterocyclic ring may be fused to one or more other carbocyclic or heterocyclic rings; X is a neutral or negatively charged N- or S- donor ligand; Y is a counterion; m is 0 or 1; q is 1, 2 or 3; C' is C1-12 alkylene bound to two A groups; p is 0 or 1 and r is 1 when p is 0 and r is 2 when p is 1; and A and B are each independently O-donor, N-donor or S-donor ligands, and may be connected to one another. The compounds are used in cancer therapy.

Description

ARENE RUTHENIUM (II) COMPOUNDS AND THEIR USE IN CANCER THERAPY

The present invention relates to ruthenium (II) compounds, in particular their use in medicaments for the treatment and / or prophylaxis of cancer and methods for their preparation.

WO 01/30790 and WO 02/02572 disclose ruthenium (II) compounds for use in the treatment of cancer. These compounds may be described as half-sandwich compounds having an arene ring bonded to ruthenium and other non-arene ligands. The compounds exemplified in these applications have halo atoms as one of the ligands. Without wishing to be bound by theory, it is believed that hydrolysis of halo atoms activates the complex and binds the complex to DNA.

The inventors have studied the rate of hydrolysis of many different ligands, including halo, and surprisingly found that complexes containing ligands with longer hydrolysis times still exert antitumor activity.

According to the present invention there is provided a ruthenium (II) compound of formula (I), or a solvate or prodrug thereof:

In the formula,

^{R 1, R 2, R 3} , R 4, R 5 and R ⁶ is H, C _{1 -7} alkyl, C _{5 -20} aryl, C _{3 -20} heterocyclyl, halo, ester, amido, acyl, sulfo Independently selected from sulfonamido, ether, thioether, azo, amino, or R ¹ and R ² together with the ring to which they are attached contain up to three 3- to 8-membered carbocyclic or heterocyclic rings Forming a saturated or unsaturated carbocyclic or heterocyclic group wherein the carbocyclic or heterocyclic ring can each be fused to one or more other carbocyclic or heterocyclic rings;

X is a neutral or negatively charged N- or S-donor ligand;

Y is a counter ion;

m is 0 or 1;

q is 1, 2 or 3;

C 'is bonded to two of the A _{1 -12} C alkylene;

p is 0 or 1, r is 1 when p is 0, and r is 2 when p is 1;

A and B are each independently O-donor, N-donor or S-donor ligand.

When p is 1, ligand A is bound to another ligand A such that the compound contains two ruthenium atoms. Such complexes are called dinuclear complexes.

Ligands A and B may be linked to each other, but they may not be bound to ligand X.

A second aspect of the present invention provides a composition comprising the compound of the first aspect and a pharmaceutically acceptable carrier or diluent.

A third aspect of the invention provides the use of a compound of the first aspect in a method of treatment.

A fourth aspect of the present invention provides the use of the compound of the first aspect, in the manufacture of a medicament for the treatment of cancer.

A fifth aspect of the present invention provides a method of treating a subject suffering from cancer, the method comprising administering to said subject a therapeutically effective amount of a compound of said first aspect in the form of a pharmaceutical composition.

Justice

N-donor ligand: An N-donor ligand is a ligand which binds to a metal atom via a nitrogen atom. These are well known in the art and include nitrile ligands (N≡CR); Azo ligands (N = NR); Aromatic N-donor ligands; Amine ligands (NR ^N1 R ^N2 R ^N3 ); Azide (N ₃ ⁻ ); Cyanide (N≡C ⁻ ); Isothiocyanate (NCS ⁻ ).

In both nitrile and azo ligands, R may be selected from C _{1 -7} alkyl and C _{5 -20} aryl. Aromatic N-donor ligands include optionally substituted pyridine, pyridazine, pyrimidine, purine and pyrazine. Optional substituents may be selected from cyano, halo, and C _{1 -7} alkyl.

R ^N1, R ^N2 and R ^N3 may be independently selected from H and C _{1 -7} alkyl, or when A and B are both amine ligands, R ^N1 of each ligand is bonded to C _{1 -7} alkyl with alkylene To form a chain.

when p is 1, R ^N2 each phase A ligand is combined together to form a C _{1 -12} alkylene C '.

S-donor ligands: S-donor ligands are ligands that are bound to metal atoms via sulfur atoms. These are well known in the art and include thiosulfate (S ₂ O ₃ ^{2 −} ); Isothiocyanate (NCS ^-); Thiocyanate (CNS ^-); Sulfoxide ligands (R ^S1 R ^S2 SO); Thioether ligands (R ^S1 R ^S2 S); Thiolate ligands (R ^S1 S ⁻ ); Sulfinate ligands (R ^S1 SO ₂ ⁻ ); And seolpe carbonate ligand acids (R ^S1 SO ^-) and contains, in which R ^S1 and R ^S2 are independently selected from C _{1 -7} alkyl and C _{5 -20} aryl group, these groups may be optionally substituted.

O-donor ligand: An O-donor ligand is a ligand bound to a metal atom via an oxygen atom. These are well known in the art and include carbonates (CO ₃ ⁻ ); Carboxylate ligands (R ^C CO ₂ ⁻ ); Nitrate (NO ₃ ⁻ ); Sulfate (SO ₄ ^{2 -),} and sulfonate (R ^S1 O ₃ ^-) it includes, where R ^C is C ₁ alkyl and C _{-7 -20 5} is selected from aryl, R ^S1 is as defined above.

C _{1 -7} alkyl: The term as used herein, "C _{1 -7} alkyl" as one obtained by removing a hydrogen atom from a carbon atom of a carbon number of 1 to 7 hydrocarbon compound corresponding to the part, and this It may be saturated or unsaturated (eg partially unsaturated, fully unsaturated). Thus, the term "alkyl" includes subclasses of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, and the like, as described below.

An example of a saturated C _{1 -7} alkyl group is methyl (C _1), ethyl (C _2), propyl (C _3), butyl (C _4), pentyl (C _5), hexyl (C ₆₎ and heptyl (C ₇₎ Although these are mentioned, It is not limited to these.

Examples of saturated linear C _{1 -7} alkyl group is methyl (C _1), ethyl (C _2), n- propyl (C _3), n- butyl (C _4), n- pentyl (amyl) (C _5), n -Hexyl (C ₆ ) and n-heptyl (C ₇ ), although not limited thereto. C ₁ of saturated branched _{- 7} Examples of alkyl groups include iso-propyl (C _3), iso-butyl (C _4), sec- butyl (C _4), tert- butyl (C _4), iso-pentyl (C ₅ ) And neo-pentyl (C ₅ ).

C _{2 -7} alkenyl: The term "C _{2 -7} alkenyl" as used herein is a carbon to carbon double bond with the corresponding one or more alkyl groups. Examples of the C _{2 -7} alkenyl group is ethenyl (vinyl, -CH = CH _2), 1- propenyl _{(-CH = CH-CH 3)} , 2- propenyl (allyl, -CH-CH = CH ₂₎ , Isopropenyl (1-methylvinyl, -C (CH ₃ ) = CH ₂ ), butenyl (C ₄ ), pentenyl (C ₅ ) and hexenyl (C ₆ ), but are not limited thereto It is not.

C _{2 -7} alkynyl: The term as used herein in "C _{2 -7-alkynyl"} is a carbon to the carbon-carbon triple bond in the alkyl group with one or more of them. C _{2 -7} be mentioned an alkynyl group is (-C≡CH) and 2-propynyl (propargyl, -CH ₂ -C≡CH) ethynyl] Examples of, but not limited to these.

C _{3 -7-cycloalkyl:} The term as used herein, "C _{3 -7-cycloalkyl"} is also a group-cycle group; That is, it corresponds to the monovalent portion obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, where the carbocyclic ring may be saturated or unsaturated (eg, partially unsaturated, fully unsaturated). This part has 3 to 7 carbon atoms. Accordingly, the term "C _{3 -7-cycloalkyl"} includes the sub-classes cycloalkenyl and cycloalkyl alkynyl. Examples of cycloalkyl groups include saturated hydrocarbon compounds [ie, cyclopropane (C ₃ ), cyclobutane (C ₄ ), cyclopentane (C ₅ ), cyclohexane (C ₆ ), cycloheptane (C ₇ ), methylcyclopropane ( C ₄ ), dimethylcyclopropane (C ₅ ), methylcyclobutane (C ₅ ), dimethylcyclobutane (C ₆ ), methylcyclopentane (C ₆ ), dimethylcyclopentane (C ₇ ), methylcyclohexane (C ₇ )]; And unsaturated hydrocarbon compounds [ie cyclopropene (C ₃ ), cyclobutene (C ₄ ), cyclopentene (C ₅ ), cyclohexene (C ₆ ), methylcyclopropene (C ₄ ), dimethylcyclopropene ( C ₅ ), methylcyclobutene (C ₅ ), dimethylcyclobutene (C ₆ ), methylcyclopentene (C ₆ ), dimethylcyclopentene (C ₇ )], but are not limited to these. .

The alkyl group in the compound of the present invention may be optionally substituted. Substituent is a substituent containing, for example, the additional one or more additional alkyl groups and / or one or more of, C _{5 -20} aryl group (e.g., benzyl), C _{3 -20} heterocyclyl, cyano (-CN), Nitro (-NO ₂ ), hydroxyl (-OH), ester, halo, thiol (-SH), thioether and sulfonate (-S (= O) ₂ ) OR, wherein R is a sulfonate substituent, eg instance, the C _{1 -7} alkyl, C _{3 -20} heterocyclyl group or C _5-20 aryl group, preferably including C _{1 -7} alkyl group)).

C _{2 -12} alkylene: The term "C _{2 -12} alkylene" but is defined similarly to the definition of the term "alkyl", and comprises a C ₂ to C _12, for example two or more (for example, connected to the chain, 2 Divalent species with radicals separated by from 12 to 12 carbon atoms. Preferably, the alkylene group is a straight chain group. C _{2 -12} alkylene group is preferably alkylene least one phenyl in the alkylene chain (e.g., 1,4-phenylene) and / or -CONR ^1a - groups and / or -NR ^2a - groups, optionally by It may be optionally substituted, wherein R ^1a and R ^2a represents a H, C _{1 -7} alkyl, C _{3 -20} heterocyclyl or C _{5 -20} aryl independently. Preferably, R ^1a and R ^2a are H or C ₁ to C ₃ alkyl.

C _{5 -20} aryl: The term as used herein, "C _{5 -20} aryl", and one obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound corresponds to the portion, the portion is 3 to 20 ring Has an atom Preferably each ring atom has 5 to 7 ring atoms.

In the context of the present specification, the prefixes (e.g., C _{3 -20, -7} C _5, C _{5 -6,} etc.) is the number or range of number of ring atoms of ring atoms, whether carbon atoms or any heteroatoms it means. For example, the term as used herein, "aryl C _{-6 5"} corresponds to an aryl group having 5 or 6 ring atoms.

The ring atoms can all be carbon atoms as in the "carboaryl group". Examples of the aryl group include C _{3 -20} carbonyl aryl carbonyl, C _{5 -20} aryl carbonyl, C _{5 -15} aryl carbonyl, C _{5 -12} aryl carbonyl, C _{5 -10} aryl carbonyl, aryl carbonyl _-7 C _5, C _{5 -6} carboaryl, C ₅ carboaryl and C ₆ carboaryl.

Examples of carboaryl groups include benzene (ie phenyl) (C ₆ ), naphthalene (C ₁₀ ), azulene (C ₁₀ ), anthracene (C ₁₄ ), phenanthrene (C ₁₄ ), naphthacene (C ₁₈ ) and but it includes those derived from pyrene (C _16), not limited to these.

Examples of aryl groups that include fused rings, at least one of which is an aromatic ring, include indane (eg, 2,3-dihydro-1H-indene) (C ₉ ), indene (C ₉ ), isoindene ( C ₉ ), tetralin (1,2,3,4-tetrahydronaphthalene (C ₁₀ ), acenaphthene (C ₁₂ ), fluorene (C ₁₃ ), phenylene (C ₁₃ ), acefenanthrene (C ₁₅ ) And aceanthrene (C ₁₆ ), but are not limited to these.

Alternatively, the ring atom may comprise one or more heteroatoms as in a "heteroaryl group". Examples of heteroaryl groups include C _{3 -20} heteroaryl, C ₅ heteroaryl _{-20, -15} C ₅ heteroaryl, C ₅ heteroaryl _{-12, -10} C ₅ heteroaryl, C _{5 -7} heteroaryl, C _{5 -6} heteroaryl, C ₅ heteroaryl and C ₆ heteroaryl.

Examples of monocyclic heteroaryl groups include

N ₁ : pyrrole (azole) (C ₅ ), pyridine (azine) (C ₆ );

O ₁ : furan (oxol) (C ₅ );

S ₁ : thiophene (thiol) (C ₅ );

N ₁ O ₁ : oxazole (C ₅ ), isoxazole (C ₅ ), isooxazine (C ₆ );

N ₂ O ₁ : oxadiazole (furazane) (C ₅ );

N ₃ O ₁ : oxatriazole (C ₅ );

N ₁ S ₁ : thiazole (C ₅ ), isothiazole (C ₅ );

N ₂ : imidazole (1,3-diazole) (C ₅ ), pyrazole (1,2-diazole) (C ₅ ), pyridazine (1,2-diazine) (C ₆ ), pyrimidine (1,3-diazine) (C ₆ ) (eg, cytosine, thymine, uracil), pyrazine (1,4-diazine) (C ₆ );

N ₃ : triazole (C ₅ ), triazine (C ₆ ); And

N4: tetrazole (C ₅ )

Although derived from, it is not limited to these.

Examples of heteroaryl groups containing fused rings include

Benzofuran (O _1), isopropyl benzofuran (O _1), indole (N _1), isoindole (N _1), indole-lysine (N _1), indoline (N _1), turning the iso (N _1), Purine (N ₄ ) (eg, adenine, guanine), benzimidazole (N ₂ ), indazole (N ₂ ), benzoxazole (N ₁ O ₁ ), benzisoxazole (N ₁ O ₁ ), Benzodioxol (O ₂ ), Benzofurazane (N ₂ O ₁ ), Benzotriazole (N ₃ ), Benzothiofuran (S ₁ ), Benzothiazole (N ₁ S ₁ ), Benzothiadiazole (N C ₉ heteroaryl groups derived from ₂ S) (with two fused rings);

Chromene (O _1), iso-chromene (O _1), chroman (O _1), iso-chroman (O _1), benzodioxane (O _2), quinoline (N _1), isoquinoline (N ₁₎ , quinolinyl binary (N _1), benzoxazine (N ₁ O _1), benzo diazine (N _2), pyrido pyridine (N _2), quinoxaline (N _2), quinazoline (N _2), new Quinoline (N _2), phthalimide-triazine (N _2), naphthyridine (N _2), Terry Dean a C ₁₀ heteroaryl groups (jinim two fused rings) derived from an (N _4);

C ₁₁ heteroaryl groups having two fused rings derived from benzodiazepines (N ₂ );

C ₁₃ derived from carbazole (N ₁ ), dibenzofuran (O ₁ ), dibenzothiophene (S ₁ ), carboline (N ₂ ), perimidine (N ₂ ), pyridoindole (N ₂ ) Heteroaryl groups (with three fused rings); And

Acridine (N ₁ ), xanthene (O ₁ ), thioxanthene (S ₁ ), oxanthrene (O ₂ ), phenoxatiin (O ₁ S ₁ ), phenazine (N ₂ ), phenoxazine C derived from (N ₁ O ₁ ), phenothiazine (N ₁ S ₁ ), thianthrene (S ₂ ), phenanthridine (N ₁ ), phenanthroline (N ₂ ), phenazine (N ₂ ) ₁₄ heteroaryl groups (with three fused rings)

Although these are mentioned, It is not limited to these.

C _{5 -20} aryl group, for example C _{1 -7} alkyl, C _{5 -20} aryl, C _{3 -20} heterocyclyl, cyano, nitro, hydroxyl, ester, halo, thiol, thioether and sulfonate containing Optionally substituted by one or more substituents.

C _{3 -20} heterocyclyl: The term "C _{3 -20} heterocyclyl" as used herein corresponds to the first portion obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, and the portion 3 Having from 20 ring atoms, 1-10 of which are ring heteroatoms. Preferably, each ring has 3 to 7 ring atoms, of which 1 to 4 are ring heteroatoms.

In the context of the present specification, the prefixes (e.g., C _{3 -20, -7} C _3, C _{5 -6,} etc.) is the number or range of number of ring atoms of ring atoms, whether carbon atoms or heteroatoms do. For example, the term as used herein, "C _{5 - 6} heterocyclyl" are the groups heterocyclyl having 5 or 6 ring atoms. An example of a heterocyclyl group is a C _{3 -20} heterocyclyl, C _{5 -20} heterocyclyl, C _{3 -15} heterocyclyl, C _{5 -15} heterocyclyl, C _{3 -12} heterocyclyl, C _5-12 there may be mentioned heterocyclyl, C _{3 -10} heterocyclyl, C _{5 -10} heterocyclyl, C _{3 -7-heterocyclyl,} C _{5 -7} heterocyclyl and C _{5 -6} heterocyclyl.

Examples of monocyclic heterocyclyl groups include

N ₁ : aziridine (C ₃ ), azetidine (C ₄ ), pyrrolidine (tetrahydropyrrole) (C ₅ ), pyrroline (eg 3-pyrroline, 2,5-dihydropyrrole) (C ₅ ), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C ₅ ), piperidine (C ₆ ), dihydropyridine (C ₆ ), tetrahydropyridine (C ₆ ), azepine (C ₇ );

O ₁ : oxirane (C ₃ ), oxetane (C ₄ ), oxolane (tetrahydrofuran) (C ₅ ), oxol (dihydrofuran) (C ₅ ), oxane (tetrahydropyran) (C ₆ ) , Dihydropyran (C ₆ ), pyran (C ₆ ), oxepin (C ₇ );

S _1: tiran (thiirane) (C _3), thietane (C _4), tiolran (tetrahydro-thiophene) (C _5), Tian (tetrahydro-thiopyran) (C _6), thienyl plate (C _7);

O ₂ : dioxolane (C ₅ ), dioxane (C ₆ ) and dioxepane (C ₇ );

O ₃ : trioxane (C ₆ );

N ₂ : imidazolidine (C ₅ ), pyrazolidine (diazolidine) (C ₅ ), imidazoline (C ₅ ), pyrazoline (dihydropyrazole) (C ₅ ), piperazine (C ₆ );

N ₁ O ₁ : tetrahydrooxazole (C ₅ ), dihydrooxazole (C ₅ ), tetrahydroisoxazole (C ₅ ), dihydroisoxazole (C ₅ ), morpholine (C ₆ ), tetrahydro Oxazine (C ₆ ), dihydrooxazine (C ₆ ), oxazine (C ₆ );

N ₁ S ₁ : thiazolin (C ₅ ), thiazolidine (C ₅ ), thiomorpholine (C ₆ );

N ₂ O ₁ : oxadiazine (C ₆ );

O ₁ S ₁ : oxathiol (C ₅ ) and oxatian (thioxane) (C ₆ ); And

N ₁ O ₁ S ₁ : oxathiazine (C ₆ )

And those derived from, but are not limited to these.

C _{3 -20} heterocyclyl group, for example, C _{1 -7} alkyl, C _{5 -20} aryl, C _{3 -20} heterocyclyl, cyano, nitro, hydroxyl, ester, halo, thiol, thioether and sulfonate Optionally substituted by one or more substituents including nates.

Halo: -F, -Cl, -Br and -I.

Ester (carboxylate, carboxylic acid ester, butyloxycarbonyl): -C (= O) OR ( wherein, R is an ester substituent, for example, C _{1 -7} alkyl, C _{3 -20} heterocyclyl group or a _5- C ₂₀ aryl group, and is preferably a C _{1 -7} alkyl group). Examples of other ester groups include -C (= 0) OCH ₃ , -C (= 0) OCH ₂ CH ₃ , -C (= 0) OC (CH ₃ ) ₃ and -C (= 0) OPh. It is not limited to these.

Amino: also known as _{7-alkylamino -} -NR ¹ R ² (wherein, R ¹ and R ² are independently amino substituents, for example, hydrogen, C _{1 -7} alkyl group (C _{1 - 7} alkylamino or di -C ₁ hereinafter), C _{3 -20} heterocyclyl group, or C _{5 -20} aryl group, preferably H or C _{1 -7} alkyl group or, or, "cyclic" amino group, if a, R ¹ and R ² is a nitrogen atom to which they are attached Together with a heterocyclic ring having 4 to 8 ring atoms. The amino group can be primary (-NH ₂ ), secondary (-NHR ¹ ) or tertiary (-NHR ¹ R ² ), and in cationic form, can be quaternary (- ⁺ NR ¹ R ² R ³ ) have. Examples of amino groups include -NH ₂ , -NHCH ₃ , -NHC (CH ₃ ) ₂ , -N (CH ₃ ) ₂ , -N (CH ₂ CH ₃ ) ₂ , -NHCH ₂ Ph and -NHPh, It is not limited to these.

Examples of the cyclic amino group include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino and thiomorpholino.

Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C (= 0) NR ¹ R ² , wherein R ¹ and R ² are independently amino substituents as defined for amino groups ). Examples of amido groups are those in which R ¹ and R ² together with the nitrogen atom to which they are attached, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl and piperazinocarbonyl As well as amido groups that form -C (= 0) NH ₂ , -C (= 0) NHCH ₃ , -C (= 0) N (CH ₃ ) ₂ , -C (= 0) NHCH ₂ CH ₃ and -C (= O) N (CH 2 CH 3) there can be _two, but is not limited to these.

Acyl (keto): -C (= 0) R [ wherein, R is (also referred to as C _{1 -7} alkyl, acyl or C _{1 -7} alkanoyl) acyl substituent, for example, C _{1 -7} alkyl, C _{3 -20} heterocyclyl group (also referred to as C _{3 -20} acyl heterocyclyl), or C _{5 -20} aryl group (also referred to as C _{5 -20} aryl acyl group), preferably C _{1 -7} alkyl group. Examples of acyl groups include -C (= 0) CH ₃ (acetyl), -C (= 0) CH ₂ CH ₃ (propionyl), -C (= 0) C (CH ₃ ) ₃ (t-butyryl) And -C (= 0) Ph (benzoyl, phenone), although not limited thereto.

Sulfo: -S (= 0) ₂ OH, -SO ₃ H.

Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): -S (= O) ₂ NR ¹ R ² , wherein R ¹ and R ² are independently amino substituents as defined for amino groups . Examples of sulfonamido groups include -S (= O) ₂ NH ₂ , -S (= O) ₂ NH (CH ₃ ), -S (= O) ₂ N (CH ₃ ) ₂ , -S (= O) _{2 NH (CH 2 CH 3),} -S (= O) 2 N (CH 2 CH 3) 2 , and there can be a -S (= O) ₂ NHPh, not limited to these.

Ether: -OR, also known as [wherein, R is an ether substituent, for example, C _{1 -7} alkyl group (C _{1 -7} alkoxy group, also known as hereinafter), C _{3 -20} heterocyclyl group (C _{3 -20} heterocyclic group rilok quot;), or C _{5 -20} aryl group (C _{5 -20} aryloxy group, also known as quot;), preferably a C _{1 -7} alkyl group.

Thioether (sulfide): -SR [wherein, R is a thioether substituent, for example, (also referred to as C _{1 -7} alkylthio) C _{1 -7} alkyl, C _{3 -20} heterocyclyl group or a C _{5 - 20} aryl group, and is preferably a C _{1 -7} alkyl group. Examples of the C _{1 -7} alkylthio group, but include an -SCH ₃ and -SCH ₂ CH _3, not limited to these.

Azo: -N = NR (wherein, R is an azo substituent being, for example, C _{1 -7} alkyl, C _{3 -20} heterocyclyl group, or C _{5 -20} aryl group, preferably a C _{1 -7} alkyl) . Examples of azo groups include, but are not limited to, -N = N-CH ₃ and -N = N-Ph.

Heterocyclic Rings: As used herein, the term “heterocyclic ring” means 3-, 4-, 5-, 6-, 7- or 8- (preferably 5-, 6- or 7-) membered saturation Or unsaturated rings, which may be aromatic or nonaromatic, for example indole, containing one to three heteroatoms independently selected from N, O and S (see above).

Carbocyclic rings: As used herein, the term "carbocyclic ring" means a saturated or unsaturated ring, which is an aromatic containing 3 to 8 carbon atoms (preferably 5 to 7 carbon atoms) or It may be non-aromatic and includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane (see above).

Involving other forms

Unless stated otherwise, included above are the well known ionic, solvate and protected forms of these substituents. For example, it relates to carboxylic acid (-COOH), as well as conventional protected forms its anionic (carboxylate) form (-COO ^-), also it includes or solvate. Likewise, reference to amino groups includes not only the conventional protected forms of amino groups, but also the protonated forms of amino groups (-N ⁺ HR ¹ R ² ) or solvates. Likewise, on the hydroxyl groups, as well as conventional protected forms its anionic form (-O ^-) is also included.

Isomer

Optional compounds are cis- and trans-forms; E- and Z-forms; c-, t- and r-forms; Endo- and exo-forms; R-, S- and meso-forms; D- and L-forms; d- and l-forms; (+) And (-) forms; Keto-, enol- and enolate-forms; syn- and anti-forms; Synclinal-anticlinal-form; α- and β-forms; Axial and horizontal forms; Boat-, chair-, twist-, envelope- and halfchair-forms; And one or more specific geometric isomers, optical isomers, enantiomers, diastereomers, epimeric isomers, atropic isomers, stereoisomers, tautomers, form isomers, including but not limited to combination forms thereof conformational) or anomer isomer forms, which are collectively referred to herein as "isomers" (or "isomer forms").

Except as described below for tautomeric forms, specifically excluded from the term “isomer” as used herein is a structural (or constituent) isomer (ie, rather than merely by position of an atom in space). Note that the relationships between atoms are different isomers). For example, the methoxy group -OCH ₃ relates to the hydroxymethyl group -CH ₂ OH which is a structural isomer thereof and should not be inferred. Likewise, ortho-chlorophenyl should not be inferred as to its structural isomer, meta-chlorophenyl. However, it relates to a class of structures may be well containing a structural isomeric form belonging to the class (e.g., C _{1 - 7} alkyl is n- propyl and iso-propyl, and including; is n- butyl, iso -, sec- and tert-butyl; methoxyphenyl includes ortho-, meta- and para-methoxyphenyl).

The exception is tautomeric forms, for example the following tautomeric pairs, ie keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime As in thioketone / enethiol, N-nitroso / hydroxyazo and nitro / aci-nitro, for example, it does not correspond to the keto-, enol- and enolate-forms.

However, specifically included in the term “isomer” are compounds by one or more isotopic substitutions. For example, H can be in any isotopic form, including ¹ H, ² H (D) and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C and ¹⁴ C; O may be in any isotopic form, including ¹⁶ O and ¹⁸ O, and the like.

Unless stated otherwise, reference to certain compounds includes all such isomeric forms, including (in whole or in part) racemic and other mixtures thereof, eg, mixtures enriched in one enantiomer. Methods for the preparation (eg asymmetric synthesis) and separation (eg, fractional crystallization and chromatographic means) of such isomeric forms are known in the art or in a manner known herein or in the manner described herein. It is easily obtained by adapting.

Solvate

It may be convenient and desirable to prepare, purify and / or handle the corresponding solvates of the active compounds. The term "solvate" is used herein to mean a complex of a solute (eg, active compound, salt of active compound) and solvent in a conventional sense. When the solvent is water, solvates can usually mean hydrates such as 1-hydrate, 2-hydrate, 3-hydrate, and the like.

Unless otherwise stated, reference to a particular compound also includes its solvate forms.

Chemically protected forms

It may be convenient or desirable to prepare, purify and / or handle the active compound in chemically protected form. The term “chemically protected form” is used herein in its ordinary chemical meaning, where one or more reactive functional groups are protected from undesirable chemical reactions under certain conditions (eg, pH, temperature, radiation, solvents, etc.). Corresponds to the compound. Indeed, well known chemical methods are used to impart non-reactivity back to functional groups which may be reactive under certain conditions. In chemically protected form, the at least one reactive functional group is in the form of a protected or protected group (also known as a concealed or concealed group or a blocked or blocked group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be carried out without adversely affecting the protected group; The protecting group can usually be removed in a subsequent step without substantially adversely affecting the rest of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

Unless otherwise stated, reference to a specific compound also includes its chemically protected forms.

Such a wide variety of "protection", "blocking" or "hiding" methods are widely used and well known in organic synthesis. For example, two non-equivalent reactive functional groups, both of which may be reactive under certain conditions, may be induced to “protect” one of the functional groups and thus to be non-reactive under certain conditions; Such protected compounds can be used as reactants that effectively have only one reactive functional group. After the desired reaction (including other functional groups) is terminated, the protected group can be “deprotected” to restore its original functionality.

For example, the hydroxy group is ether (-OR) or ester (-OC (= 0) R), for example t-butyl ether; Benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; Trimethylsilyl or t-butyldimethylsilyl ether; Or acetyl esters (-OC (= 0) CH ₃ , -OAc).

For example, an aldehyde or ketone group may be protected as acetal (R-CH (OR) ₂ ) or ketal (R ₂ C (OR) ₂ ), respectively, wherein the carbonyl group (> C═O) is for example It is converted to diether (> C (0R) ₂ ) by reaction with primary alcohol. Aldehyde or ketone groups are easily regenerated by hydrolysis with excess water in the presence of an acid.

For example, amine groups are, for example, amides (-NRCO-R) or urethanes (-NRCO-OR), for example methyl amides (-NHCO-CH ₃ ); As benzyloxy amide (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz); as t-butoxy amide (-NHCO-OC (CH ₃ ) ₃ , -NH-Boc); As 2-biphenyl-2-propoxy amide (-NHCO-OC (CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ , -NH-Bpoc), 9-fluorenylmethoxy amide (-NH-Fmoc), 6-nitroveratriryloxy amide (-NH-Nvoc), 2-trimethylsilylethyloxy amide (-NH-Teoc), 2,2,2-trichloroethyloxy amide (-NH-Troc), allyl As oxy amide (-NH-Alloc), as 2 (-phenylsulfonyl) ethyloxy amide (-NH-Psec); Or as appropriate (e.g., cyclic amines), as a nitroxide radical (> NO.).

For example, a carboxylic acid group as an ester, for example, C _{1 - 7} alkyl ester (e.g., methyl ester; t- butyl ester); C _{1 - 7} haloalkyl ester (e.g., C _{1 - 7} alkyl ester to a tree); Tree C _{1 - 7} alkyl silyl -C _{1 - 7} alkyl ester; A, (nitrobenzyl ester such as benzyl ester) or C _{5 - - 20} aryl -C _{1 7} alkyl ester; Or as an amide, for example as methyl amide.

For example, thiol groups are thioethers (-SR), for example benzyl thioethers; It may be protected as acetamidomethyl ether (—S—CH ₂ NHC (═O) CH ₃ ).

Prodrug

It may be convenient or desirable to prepare, purify and / or handle the active compound in prodrug form. As used herein, the term “prodrug” corresponds to a compound that, when metabolized (eg in vivo), yields the desired active compound. Typically, prodrugs are inactive or less active than the active compound but can provide advantageous handling, administration or metabolic properties.

Unless otherwise stated, reference to a particular compound also includes its prodrugs.

For example, some prodrugs are esters of active compounds (eg, physiologically acceptable metabolic labile esters). During metabolism, the ester group (-C (= 0) OR) is cleaved to obtain the active drug. Such esters may be formed by esterification of any of the carboxylic acid groups (—C (═O) OH) in the parent compound, if appropriate, before the protection of any other reactive groups present in the parent compound. After that, it may be deprotected as necessary.

Examples of such metabolically labile esters are those of the formula —C (═O) OR, where R is

C _{1 - 7} alkyl,

(Eg, -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);

C _{1 - 7} alkyl amino

(Eg, aminoethyl; 2- (N, N-diethylamino) ethyl; 2- (4-morpholino) ethyl); And

Acyloxy -C _{1 - 7} alkyl,

(Eg, acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;

1-acetoxyethyl; 1- (1-methoxy-1-methyl) ethyl-carbonyloxyethyl; 1- (benzoyloxy) ethyl;

Isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl;

Cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl;

Cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl;

(4-tetrahydropyranyloxy) carbonyloxymethyl;

1- (4-tetrahydropyranyloxy) carbonyloxyethyl;

(4-tetrahydropyranyl) carbonyloxymethyl; And

1- (4-tetrahydropyranyl) carbonyloxyethyl).

In addition, some prodrugs are enzymatically activated to yield the active compound, or upon further chemical reaction to yield the active compound (eg, as ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Use of Compounds of the Invention

The present invention provides a compound of formula (I), or a solvate or prodrug thereof (“active compound”) for use in a method of treating an animal or human body. Such methods may comprise administering to the subject a therapeutically effective amount of the active compound, preferably in the form of a pharmaceutical composition.

The term "treatment" as used herein in the treatment of a condition generally refers to, for example, inhibition of the progression of a condition, whether human or animal (eg, in veterinary applications). Corresponding to the treatments and therapies at which the desired desired therapeutic effect is achieved, including the reduction of the rate of progression, the cessation of the rate of progression, the improvement of the condition and the healing of the condition. Treatment as a prophylactic (ie prophylactic) is also included.

As used herein, the term “therapeutically effective amount” refers to an active compound, or substance, composition or composition comprising the active compound, which is effective to produce any desired therapeutic effect corresponding to a suitable benefit / risk ratio. Corresponding to such amounts of formulation.

administration

The active compound or pharmaceutical composition comprising the active compound may be administered orally (eg, by ingestion), regardless of systemic / peripheral or site of action desired; Topical (including, for example, transdermal, intranasal, intraocular, oral and sublingual); Lungs (eg, using aerosols, for example by inhalation or aeration through the mouth or nose); rectal; quality; For example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intradermal, intrathecal, intracapsular, subcapsular, orbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, Parenteral by injection, including subarachnoid and intrasternal; For example, it may be administered to a subject by any convenient route of administration, including but not limited to parenteral by implantation of depots subcutaneously or intramuscularly.

Subjects are eukaryotes, animals, vertebrates, mammals, rodents (eg guinea pigs, hamsters, rats, mice), rats (eg mice), canines (eg dogs), feline Animals (e.g. cats), horses (e.g. horses), primates, apes (e.g. monkeys or ape), monkeys (e.g. May be a small monkey (marmoset), baboon), a tailless monkey (eg, gorilla, chimpanzee, orangutan, gibbon) or human.

Formulations ( formaulations )

The active compound may be administered alone, but at least one active compound as defined above may be added to one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, It is preferred to be present as a pharmaceutical composition (e.g., a formulation) comprising with preservatives, glidants or other substances well known to those skilled in the art and any other therapeutic or prophylactic agents.

Accordingly, the present invention relates to a pharmaceutical composition as defined above, and at least one active compound as defined above, to at least one pharmaceutically acceptable carrier, excipient, buffer, adjuvant, stabilizer or Further provided are methods for the preparation of a pharmaceutical composition comprising mixing with other materials as described.

As used herein, the term "pharmaceutically acceptable" refers to a subject (e.g., subject to an appropriate benefit / hazard ratio without excess toxicity, irritation, allergic reactions or other problems or involvement within the scope of normal medical judgment (e.g., For example, compounds, materials, compositions and / or dosage forms suitable for use in contact with tissues of humans). Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, excipients and the like can be found in standard pharmaceutical textbooks, for example, Remington's Pharmaceutical Sciences , 18th edition, Mack Publishing Company, Easton, Pa., 1990.

The formulations may normally be presented in unit dosage form and may also be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by mixing the active compounds homogeneously and intimately with the carrier or by finely dividing the solid carrier or both, followed by shaping the product if necessary.

Formulations include liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, suppositories, ointments, It may be in the form of gels, pastas, creams, sprays, sprays, mists, blowing agents, lotions, oils, boluses, electuaries or aerosols.

Formulations suitable for oral administration (eg by ingestion) may be presented as discrete units, such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; As a powder or granules; As a liquid or suspending agent in an aqueous or non-aqueous liquid; Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; As a cyclic agent; As a paper; Or as pasta.

Tablets may be prepared by conventional means, eg, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may include one or more binders (eg, povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); Fillers or diluents (eg, lactose, microcrystalline cellulose, calcium hydrogen phosphate); Lubricants (eg, magnesium stearate, talc, silica); Disintegrants (eg sodium starch glycolate, crosslinked povidone, crosslinked carboxymethylcellulose sodium); Surfactants or dispersants or wetting agents (eg, sodium lauryl sulfate); And free-flowing forms of the active compounds, such as powders or granules, optionally mixed with preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid) in a suitable machine. By compression. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets may be optionally coated or scored, and also, for example, hydroxypropylmethylcellulose may be used in various proportions to provide a desired release profile to provide sustained or controlled release of the active compound. It can be formulated to. The tablet may optionally have an enteric coating formed to be released in parts of the intestine other than the stomach.

Formulations suitable for topical administration (eg, transdermal, intranasal, intraocular, oral and sublingual) may include ointments, creams, suspensions, lotions, powders, solutions, pastas, gels, sprays, aerosols or It can be formulated as an oil. Alternatively, the formulation may comprise a patch or dressing such as a bandage or bandage impregnated with the active compound and optionally one or more excipients or diluents.

Formulations suitable for topical administration in the oral cavity include lozenges comprising the active compound in a spice base, conventional sucrose and acacia or tragacanth; Pastilles comprising the active compound in an inert base such as gelatin and glycerin or sucrose and acacia; And mouthwashes comprising the active compound in a suitable liquid carrier.

Formulations suitable for topical administration to the eye include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.

Formulations suitable for nasal administration in which the carrier is a solid can be administered in a nasal way, i.e., by a rapid inhalation via a nasal route from a container of powder held closely to the nose, for example in the range of about 20 to about 500 μm With coarse powder. Suitable formulations wherein the carrier is a liquid for administration such as, for example, intranasal sprays, nasal drops, or aerosol administration by nebulizers, include aqueous or oily solutions of the active compounds.

Formulations suitable for administration by inhalation are provided as aerosol sprays from a pressurized pack using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gas. Include things.

Formulations suitable for topical administration through the skin include ointments, creams and emulsions. When formulated into ointments, the active compounds may optionally be used with paraffinic or water miscible ointment bases. Alternatively, the active compound may be formulated into a cream with an oil-in-water cream base. If necessary, the cream-based water phase may contain at least 30 polyhydric alcohols, ie alcohols having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. May contain% w / w. Topical formulations may preferably include a compound that enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.

When formulated as a topical emulsion, the oil phase may optionally comprise only an emulsifier (or also known as an emulgent), or comprise at least one emulsifier and a mixture of fats or oils, or both fats and oils. can do. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also desirable to include both oils and fats. The emulsifier (s) with or without stabilizer (s) forms the so-called emulsifying wax, and the wax together with the oil and / or fat forms the so-called emulsifying ointment base which forms the oily disperse phase of the cream. .

Suitable emulsions and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate. The selection of suitable oils or fats for the formulation is based on obtaining the desired cosmetic properties because the solubility of the active compounds in most oils that are easy to use in pharmaceutical emulsions can be very low. Thus, the cream agent preferably needs to be a greasy, non-polluting and flushable product with a suitable consistency so as not to leak out of the tube or other container. Di-isoadiate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or Crodamol CAP As the above, linear or branched monobasic or dibasic alkyl esters such as blends of known branched esters can be used, the last three of which are preferred. These may be used alone or in combination according to the required properties.

Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin and other mineral oils may be used.

Formulations suitable for rectal administration may be presented as suppositories with suitable bases, including, for example, cocoa butter or salicylates.

Formulations suitable for vaginal administration may be provided as a suppository, tampon, cream, gel, pasta, foam, or spray, containing such carriers known in the art as suitable for the active compound.

Formulations suitable for parenteral administration (e.g., by injection, including skin, subcutaneous, intramuscular, intravenous and intradermal) are solutes, antioxidants, buffers, preservatives that will tonicize the blood and preparations of the intended recipients. Aqueous or non-aqueous isotonic, pyrogen-free sterile injectable solutions that may contain stabilizers and bacteriostatic agents; And aqueous and non-aqueous sterile suspending agents which may include liposomes or other particulate systems, suspending agents and thickeners designed to target the compound to blood components or one or more organs. Examples of suitable isotonic vehicles for use in such formulations include sodium chloride injection, Ringer's solution or Lactated Ringer's Injection. Typically, the concentration of active compound in the solution is from about 1 ng / ml to about 10 μg / ml, for example from about 10 ng / ml to about 1 μg / ml. The formulation may be present in unit dose or multi-dose sealed containers such as ampoules or vials and may also be lyophilized, requiring only the addition of a sterile solution carrier, eg water for injection, immediately prior to use. Lyophilized). Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The formulations may be in the form of liposomes or other particulate bases designed to target the active compound against blood components or one or more organs.

Volume

It will be appreciated that the appropriate dosages of the active compounds, and compositions comprising such active compounds, may vary from subject to subject. Determining the optimal dose will generally include balancing the level of therapeutic benefit for any risk or deleterious side effect of the treatment of the present invention. The dose level chosen depends on the activity, route of administration, time of administration, rate of excretion of the compound, duration of treatment, other drugs, compounds and / or substances used in combination, and the age, sex, weight, condition, general health of the subject. And previous history, etc., will depend on various factors. Generally, the dose will achieve local concentration at the site of action that achieves the desired effect without causing substantial harmful or deleterious side effects, but the dosage and route of administration of the compound will ultimately be at the discretion of the physician.

In vivo administration may be effective continuously or intermittently (eg, in divided doses at appropriate intervals) throughout the course of treatment in one dose. The most effective means and methods for determining the dosage are well known to those skilled in the art and will vary depending on the agent used for treatment, the therapeutic purpose, the target cells being treated and the subject being treated. Single or multiple administrations can be performed at a dose level and pattern selected by the treating physician.

In general, suitable doses of active compound range from about 100 μg to about 250 mg / body weight / day. When the active compound is a salt, ester, prodrug or the like, the dosage is calculated based on the parent compound, so that the actual weight used is proportionally increased.

cancer

Examples of cancers that can be treated with the active compound include bladder carcinoma, breast carcinoma, colorectal carcinoma (eg, colorectal carcinoma such as colorectal adenocarcinoma and colorectal adenocarcinoma), kidney carcinoma, epidermal carcinoma, liver carcinoma, lung carcinoma, eg For example, adenocarcinoma, small cell lung carcinoma and non-small cell lung carcinoma, esophageal carcinoma, gallbladder carcinoma, ovarian carcinoma, pancreatic carcinoma, for example, exocrine pancreatic carcinoma, gastric carcinoma, cervical carcinoma, thyroid carcinoma, prostate carcinoma, or skin carcinoma Carcinoma, such as, for example, squamous cell carcinoma; Hematopoietic tumors of the lymphocyte lineage, such as leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma or Burkett's lymphoma ); Hematopoietic tumors of the bone marrow lineage, such as acute and chronic myeloid leukemia, myelodysplastic syndromes or promyelocytic leukemia; Thyroid follicular cancer; Mesenchymal-derived tumors such as fibrosarcoma or rhabdomyosarcoma; Tumors of the central or peripheral nervous system, eg, astrocytoma, neuroblastoma, glioma or schwannoma; Melanoma; Testicular species; Teratocarcinoma; Osteosarcoma; Xenoderoma pigmentoum; Keratoctanthoma; Thyroid follicular cancer, Kaposi's sarcoma, etc. are mentioned, It is not limited to these.

Examples of other therapeutic agents that may be administered with the compound of formula (I) (whether concurrent or at different time intervals) include cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, mitomycin C Or isomerase inhibitors such as radiotherapy, alkylating agents, anti-metabolic agents, DNA binding agents and microtubule inhibitors (tubulin targeting agents), but are not limited thereto. For the case of active compounds in combination with other therapies, two or more treatments may be given via different routes with individually varying dose schedules.

Combination of the compounds of the present invention with the various drugs listed above will be at the discretion of the physician selecting the dose using dose regimens known to those skilled in the art and common knowledge.

When the compound of formula (I) is administered in combination with one, two, three, four or more, preferably one or two, more preferably one other therapeutic agent, the compound is administered simultaneously or sequentially Can be. When administered sequentially, they are at close spatial intervals (eg, over a period of 5 to 10 minutes) or longer intervals (eg, 1, 2, 3, 4 or more time intervals, or more if necessary). Even longer intervals) and the correct dosage regimen may correspond to the nature of the therapeutic agent (s).

Compounds of the present invention may be used for non-chemotherapy treatments such as radiation therapy, photodynamic therapy, gene therapy and the like; It may also be administered in connection with surgery and dietary control.

Preferred form

R ^One - R ⁶

In one embodiment group of the invention, R ¹ and R ² together with the ring to which they are attached form a saturated or unsaturated carbocyclic or heterocyclic group containing a 3- to 8-membered carbocyclic or heterocyclic ring, Wherein the carbocyclic or heterocyclic rings may each be fused to one or more other carbocyclic or heterocyclic rings.

In this embodiment group, R ³ , R ⁴ , R ^5, and R ⁶ are preferably H.

R ¹ and R ² in a compound of formula (I) may represent an ortho- or peri-fused carbocyclic or heterocyclic ring system with the ring to which they are bonded.

R ¹ and R ² together with the ring to which they are bound are for example a wholly carbocyclic fused ring system, such as a ring system containing two or three fused carbocyclic rings such as optionally substituted, optionally hydrogenated naphthalene or anthracene, etc. Can be represented.

Alternatively, R ¹ and R ² may represent a fused tricyclic ring of anthracene or mono, di, tri, tetra or more hydrogenated derivatives of anthracene or anthracene together with the ring to which they are bonded in the compound of formula (I). . For example, R ¹ and R ² in formula (I) may represent anthracene, 1,4-dihydroanthracene or 1,4,9,10-tetrahydroanthracene together with the ring to which they are attached.

R ¹ and R ² together with the ring to which they are bonded in formula (I) may be represented by the following chemical structural formula:

.

.

In another embodiment the ^{group, R 1, R 2, R} 3, R 4, R 5 and R ⁶ is H, C _{1 -7} alkyl, C _{5 -20} aryl, C _{3 -20} heterocyclyl, halo, ester , Amido, acyl, sulfo, sulfonamido, ether, thioether, azo and amino. In this embodiment the ^{group, R 1, R 2, R} 3, R 4, R 5 and R ⁶ is preferably H, C _{1 -7} alkyl, C _{5 -20} are independently selected from aryl and ester. Among them, H and C _{1 -7} alkyl (especially C _1-3 alkyl) is most preferred.

In the present embodiment group, ⁴ , ⁵ or ⁶ of R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are preferably hydrogen and the remaining groups (if present) are C _{1 − 7} alkyl, C _{5 -20} aryl, C _{3 -20} heterocyclyl, halo, ester, amido, acyl, sulfo, sulfonamido, ether, thioether, azo and amino, or more preferably C _{1 -7} alkyl, C _{5 -20} are selected from aryl and ester, and most preferably C _{1 -7} alkyl (especially C _1-3 alkyl). R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ When two of the groups are not H, these groups are preferably meta or para with respect to each other, and more preferably para with respect to the other.

Examples of particularly preferred substituent patterns include phenyl; 1-methyl; And 4-iso-propyl, but are not limited to these.

A and B

A and B together represent NR ^N4 R ^N5- (CR ^C1 R ^C2 ) _n -NR ^N6 R ^N7 , where R ^C1 and R ^C2 are independently selected from H and C _1-4 alkyl and R ^N4 , R ^N5 , R ^N6 and R ^N7 are independently selected from H and C _{1 -4} alkyl, n is preferably an integer of 1 to 4.

Preferably, R ¹⁴ and R ¹⁵ are both hydrogen. Preferably n is 2 or 3, more preferably 2. R ^N4 , R ^N5 , R ^N6 and R ^N7 are preferably H or methyl, more preferably R ^N4 , R ^N5 , R ^N6 and R ^N7 are all H.

P is 0 when R ^N4 is present at A. If R ^N4 is absent, p is 1 and C 'replaces R ^N4 . In one embodiment of the group, when R ^N4 is absent from A, p is 1, and, preferably, C 'is C _{4 -10} alkylene group which does not have a substituent (e.g., cyclohexylene).

Examples of the binuclear complexes of the present embodiment group are those in which pairs of A and B, together with linker C ′, are represented by the following chemical structural formula:

In formula, n ', n ", x', x", and y 'respectively independently represent the integer of 1-12, Preferably it is 1-6.

X

When X is an N-donor ligand, it is preferably selected from azide, isothiocyanate and optionally substituted pyridine ligand. Among these, azide and isothiocyanate are preferable.

When X is an optionally substituted pyridine ligand, it is preferable that this ligand is at least monosubstituted and may be disubstituted. These substituents are preferably selected from halo (eg chloro, fluoro), cyano and lower alkyl (eg methyl). Of these, chloro, cyano and methyl are preferred. Preferred substituent patterns include, but are not limited to, 3-, 5-dichloro, 4-cyano and 3-methyl.

In some embodiments, X is nitrile ligands (N = CR); Azo ligands (N = NR); Amine ligands (NR ^N1 R ^N2 R ^N3 ); Azide (N ₃ ⁻ ); Cyanide (N≡C ⁻ ); And isothiocyanate (NCS ⁻ ).

X is S- donor ligand, thiolate ligand, for example, PhS ^- preferably a.

Y ^{q -}

Y ^{q −} in the compound of formula (I) is a counterion and is present in the compound only when the complex containing the metal ion is charged. Y ^{q -} is preferably, for example, PF ₆ ^-, BF ₄ ^- is a non-nucleophilic anions, such as ^-, BPh ₄ ^- or CF ₃ SO ₂ O.

General Synthetic Method

The present invention provides a chemical formula [(η ⁶ -C ₆ (R ¹ ) (R ² ) (R ³ ) (R ⁴ ) (R ⁵ ) (R ⁶ )) RuABCl] [Y ^{q which} may be in the form of monomers or dimers. ^-] reaction with AgNO ₃ and in a solvent appropriate to the reaction compound, and then removes the AgCl, in the presence of a suitable solvent for the reaction, optionally Y ^{q -} in the presence of, or Y ^{q -} with subsequent addition of for MX and the reaction Also provided is a process for the preparation of a compound of the present invention comprising R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X, A, B and Y, with respect to the compound of the present invention As defined above, M is a suitable cation, for example Na ⁺ .

Preferred reaction conditions include the following steps:

(a) stirring the starting ruthenium complex as described above with AgNO _{3 using} a 1: 1 mixture of MeOH and H ₂ O as a solvent;

(b) filtering off the formed AgCl precipitate;

(c) adding MX (which can be dissolved by heating if necessary) and reacting;

(d) adding a compound of formula (NH ₄ ⁺ ) Y ^{q −} , for example a source of Y ^{q −} , such as NH ₄ PF _6, and evaporating the filtrate to yield the product.

The filtrate can be purified, for example, by recrystallization from acetone.

The following non-limiting examples illustrate the invention.

Common way

Electrospray ionization mass spectrometry (ESI-MS: Electrospray Ionisation Mass Spectrometry): cation-electrospray ionization mass spectra were obtained by the Platform II mass spectrometer (Micromass, Manchester, UK). For offline ESI-MS analysis, samples were prepared in 50% CH ₃ CN / 50% H ₂ O (v / v) and injected directly into the mass spectrometer at 6 μl min ⁻¹ . Ions were produced in an atmospheric pressure ionisation (API) / ESI ion source. For on-line LC-ESI-MS analysis, a Waters 2690 HPLC system was connected to the mass spectrometer using columns and gradients as described above for HPLC analysis at a flow rate of 1.0 ml min ⁻¹ and partition ratio 1/5. The spray voltage was 3.50 to 3.68 kV. The cone voltage was changed over the range of 15-30V as needed. With the nitrogen dry gas flowing at 450 Lh ⁻¹ , the capillary temperature was 338 K for direct injection and 413 K for HPLC sampling. A quadrupole analyzer operating at a background pressure of 2 × 10 ⁻⁵ Torr was scanned at 300 Da s ⁻¹ for direct injection and at 750 Da s ⁻¹ for HPLC sampling. Data was collected (for 10 scans during direct injection analysis), analyzed on a Mass Lynx (ver. 2.3) Windows NT PC data system using the Max Ent electrospray software algorithm and tested for NaI test files. The mass accuracy of all measurements was within 0.1 m / z units.

X-ray crystallography : All data were collected at 150 K on a Bruker Smart Apex CCD diffractometer equipped with Oxford Cryosystems thermostat. Direct application (Shelxs, SIR92, Dirdif) (Sheldrick, GM, SHELXS) after application of multi-scan absorption correction (SADABS) (Sheldrick, GM, SADABS, Program for carrying-out multiscan absorption corrections, University of Gottingen, Germany, 1998) and SHELXL.Programs for the solution and refinement of crystal structures, University of Gottingen, Germany, 1998; Altomare, A., et al., AJ Appl. Crystallogr., 26, 343-350 (1993); Beurskens, PT, et al., The DIRDIF96 Program System, Technical Report of the Crystallography Laboratory, University of Nijmegen, The Netherlands (1996)), interpreted all structures and tested for F ² using all data (SHELXL) (Betteridge, PW, et al., J. Appl. Cryst, 36, 1487 (2003)).

Comparative example  1: [(η ⁶ - C ₆ H ₅ C ₆ H ₅ ) Ru (en) Cl] [ PF ₆ ] ( C1 ) Synthesis

This compound is described in Morris, RE, et al., J. Med . Chem ., 44, 3616-3621 (2001) -Compound 9].

Example  1: [(η ⁶ - C ₆ H ₅ C ₆ H ₅ ) Ru (en) N ₃ ] [ PF ₆ Synthesis of (1)

This complex was prepared by refluxing complex C1 (25.0 mg, 0.0496 mmol) and AgNO ₃ (8.4 mg, 0.0494 mmol) in 2.5 ml of a 1: 1 mixture of MeOH and H ₂ O for 1 hour. AgCl was removed by filtration. NaN ₃ (163 mg, 2.51 mmol) was added, dissolved by heating and left overnight. NH ₄ PF ₆ (250 mg) was added to give a microcrystalline yellow precipitate. This precipitate was recrystallized from acetone to give a yellow crystalline product. Yield of compound 1 was 8.6 mg (34%).

Analytical Calcd for C ₁₄ F ₆ H ₁₈ N ₅ PRu: C 33.47, H 3.61, N 13.94. Found: C 33.37, H 3.46, N 13.68. MS: m / z 357.7 for [M-PF ₆ ] ⁺ (calculated: 357.1).

Comparative example  2: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) Cl] [ PF ₆ ] ( C2 ) Synthesis

This complex was prepared from [(η ⁶ -C ₆ (CH ₃ ) ₆ ) RuCl ₂ ] ₂ in a similar manner to compound C1 in Comparative Example 1. Yield of compound C2 : 68%. Analytical Calcd for C ₁₄ F ₆ H ₁₂ N ₂ ClPRu: C 33.59, H 4.43, N 5.60. Found: C 33.55, H 4.57, N 5.54.

Example  2: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru en (pyridine)] [ PF ₆ ] ₂  Synthesis of (2)

This complex was prepared by refluxing complex C2 (25.0 mg, 0.0496 mmol) and AgNO ₃ (8.4 mg, 0.0494 mmol) in 2.5 ml of a 1: 1 mixture of MeOH and H ₂ O for 1 hour. AgCl was removed by filtration. Pyridine (101 μl, 1.25 mmol) was added and the resulting mixture was left overnight. The volume was reduced to about 1.5 ml by rotary evaporation and 100 mg NH ₄ PF ₆ was added. The yellow precipitate was dissolved in acetone. This solution was then filtered and the acetone was slowly evaporated to yield a microcrystalline yellow product. Yield of 2 : 19.3 mg (56%). Anal for C ₁₉ F ₁₂ H ₃₁ N ₃ P ₂ Ru: C 32.96, H 4.51, N 6.07. Found: C 33.47, H 4.50, N 6.24.

Example  3: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) (SCN)] [ PF ₆ ] ₂  Synthesis of (3)

This complex was prepared by refluxing complex C2 (25.0 mg, 0.0496 mmol) and AgNO ₃ (7.0 mg, 0.0412 mmol) in 2.5 ml of a 1: 1 mixture of MeOH and H ₂ O for 1 hour. AgCl was removed by filtration. KSCN (243 mg, 2.50 mmol) was added and the solution was stirred for 1 day. 150 mg of KPF ₆ was added and a sufficient amount of acetone was added to dissolve the precipitate obtained. Acetone was slowly evaporated to yield yellow crystals, which were suitable for X-ray crystallographic studies. Yield: 6.9 mg (26%).

The X-ray crystal structure crystal obtained the results shown below, and it can be seen from this that isothiocyanate is bonded through a nitrogen atom.

Crystal Data and Structure Verification of Compound 3

X-ray data:

Decision data

Experimental C15 H26 F6 N3 O P Ru S

Formula weight 542.49

Crystalline system

Space County Pca21

Unit cell dimension a = 14.7411 (12) Å α = 90 °.

b = 9.0154 (7) Å β = 90 °.

c = 15.6070 (12) γ γ = 90 °.

Volume 2074.1 (3) Å ³

Z 4

Data collection

Devices Bruker Smart Apex CCD

Analysis and Verification

Analysis Patterson (Dirdif)

R1 = 0.0619 [5064 data]

Example  4: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) ( SPh )] [ PF ₆ Synthesis of (4)

This complex was prepared by refluxing complex C2 (25.0 mg, 0.0496 mmol) and AgNO ₃ (8.4 mg, 0.0494 mmol) in 2.5 ml of a 1: 1 mixture of MeOH and H ₂ O for 1 hour. AgCl was removed by filtration. NaSPh (7.9 mg, 0.0595 mmol) was added and the solution was left overnight. NH ₄ PF ₆ was added to give an orange precipitate. The acetone solution of the precipitate was slowly evaporated to give crystalline orange product and yellow powder, all of which were considered to be the title compound by mass spectrometry. Yield: 10.2 mg (36%). MS: m / z 433.0 (calculated 433.1) for [M-PF ₆ ] ⁺ .

Example  5: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) N ₃ ] [ PF ₆ Synthesis of (5)

This complex was prepared by refluxing complex C2 (25.0 mg, 0.0496 mmol) and AgNO ₃ (8.4 mg, 0.0494 mmol) in 2.5 ml of a 1: 1 mixture of MeOH and H ₂ O for 1 hour. AgCl was removed by filtration. NaN ₃ (163 mg, 2.51 mmol) was added, dissolved by heating and left overnight. NH ₄ PF ₆ (250 mg) was added to give a microcrystalline yellow precipitate. This precipitate was recrystallized from acetone to give crystalline product. Yield of compound 5 : 16.4 mg (65%). Anal for C ₁₄ F ₆ H ₂₆ N ₅ PRu: C 32.94, H 5.13, N 13.72. Found: C 32.32, H 4.45, N 12.63.

Example  6: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) (3,5- Dichloropyridine )] [ PF ₆ ] ₂  Synthesis of 6

This complex was prepared by a method similar to compound 2 in Example 2. MS: m / z 616.0 for [6-PF ₆ ] ⁺ (calculated: 616.0).

Example  7: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) (3,5- Difluoropyridine )] [ PF ₆ ] ₂  Synthesis of 7

This complex was prepared by a method similar to compound 2 in Example 2. MS: m / z 583.9 (calculated 584.1) for [7-PF ₆ ] ⁺ .

Example  8: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) (p- Cyanopyridine )] [ PF ₆ ] ₂  Synthesis of 8

This complex was prepared by a method similar to compound 2 in Example 2. MS: m / z 572.9 (calculated 573.1) for [8-PF ₆ ] ⁺ .

X-ray data:

Decision data

Experimental C20 H30 F12 N4 P2 Ru

Formula weight 717.49

Crystalline Monoclinic System

Space group P2 (1) / n

Unit cell dimension a = 8.6230 (2) Å α = 90 °

b = 34.7990 (10) Å β = 114.4360 (10) °

c = 9.8620 (3) Å γ = 90 °

Volume 2694.22 (13) Å ³

Z 4

Data collection

Absorption Correction SADABS

Analysis and Verification

Analysis Direct (SHELXS-97)

Program SHELXL-97 used for verification

R1 = 0.0575 [4950 data]

Example  9: [(η ⁶ - C ₆ ( CH ₃ ) ₆ ) Ru (en) (3- Methylpyridine )] [ PF ₆ ] ₂  Synthesis of 9

This complex was prepared by a method similar to compound 2 in Example 2. MS: m / z 562.1 (calculated 562.1) for [9-PF ₆ ] ⁺ .

X-ray data:

Decision data

Experimental C20 H27 F12 N3 P2 Ru1

Formula weight 700.45

Crystalline system

Space Army P n a 21

Unit cell dimension a = 21.3199 (6) Å α = 90 °

b = 7.7155 (2) A β = 90 °

c = 16.1809 (5) Å γ = 90 °

Volume 2661.66 Å ³

Z 4

Data collection

Absorption Correction SADABS

Analysis and Verification

Analysis Direct (SHELXS-97)

Program SHELXL-97 used for verification

R1 = 0.0444

Example  10: Analysis of Compound

Way

Ultraviolet-visible (UV- Vis) spectrometer: Perkin-Elmer Lambda-16 UV -Vis spectrophotometer was used with a quartz cuvette (0.5 ㎖) and a PTP1 Peltier temperature controller of the 1-cm path length. Spectra were processed using UVWinlab software for Windows 95.

Kinetic Study : A portion of the stock solution (4-10 mM) of the test complex in methanol was diluted with 500 μl of water and then absorbed at the selected wavelength (by hydrolysis in a 19: 1 mixture of water and methanol). Table 1 ([lambda]) was recorded at 298 K at intervals of 6-20 seconds depending on the rate of hydrolysis of each complex. The hydrolysis rate constant k _H2O for each complex is obtained by computer fit of absorbance / time data for each complex with the following first order rate equation (Equation (1)), and the results are shown in Table 1 below. It was recorded as the half life (t _1/2):

A = C ₀ + C ₁ e ^{- k t} ... Equation (1)

(Wherein C ₀ and C ₁ are computer suitability constants and A is absorbance corresponding to time t).

Cytotoxicity Research

A2780 (1st method) : A2780 cells were transplanted on the day, and the test complex was added on the 3rd day. This complex was removed on day 4 (ie 24 hour cell exposure) and propagated in fresh medium in the absence of drug, then cells were counted on day 7. The complex was stored in the dark at 277K as a precaution against photochemical degradation. IC ₅₀ (dose of compound required to cause 50% inhibition of cell proliferation) values are shown in Table 1 below.

A2780 (Second Method) and A549 : Cell lines A2780 (Human Ovarian Carcinoma, ECACC 93112519) were placed in a T-75 flask (Costar) with 5% Fetal Bovine Serum (Invitrogen), 2 mM L-Glutamine (Sigma). And RPMI-1640 (Sigma) with 1% penicillin / streptomycin (Invitrogen). Cells were passaged at approximately 75-90% confluence (1: 8 dilution) using 0.25% trypsin / EDTA (Invitrogen).

Cell line A549 (human lung carcinoma, ECACC 86012804) was prepared in T-75 flask (Costar) with DMEM (10% fetal bovine serum (Invitrogen), 2 mM L-glutamine (Invitrogen) and 1% penicillin / streptomycin (Invitrogen)). Sigma) was maintained in the medium containing. Cells were passaged at approximately 70-90% confluence (1: 8 dilution) using 0.25% trypsin / EDTA (Invitrogen).

Both cell lines were incubated at 37 ° C., 5% CO ₂ in high humidity.

A2780 carcinoma cells were seeded in 96 well plates (Nunc Maxisorp) at 5000 cells (± 10%) per well (150 μl) and incubated at 37 ° C., 5% CO ₂ in high humidity. A549 carcinoma cells were seeded in 96 well plates (Nunc Maxisorp) at 2000 (± 10%) cells per well (150 μl) and incubated for 24 hours at 37 ° C., 5% CO ₂ in high humidity.

Subject compounds were solubilized by ultrasound in DMSO (Fisher Scientific) to give 20 mM solution. Compounds were serially diluted by DMSO prior to dilution in cell medium to obtain concentrations four times higher than the final concentration required for analysis. Dilutions of the compound in the medium (50 μl) were added to the cell plate three times to obtain final concentrations of 100 μM, 50 μM, 10 μM, 5 μM, 1 μM and 0.1 μM. The final DMSO concentration in each well was 0.5% (v / v). The plates were incubated for 24 hours at 37 ° C., 5% CO ₂ in high humidity.

After incubation for 24 hours, cells were washed twice with sterile phosphate buffer saline (Sigma) (200 μl) and supplemented with cell medium (200 μl). Plates were incubated 96 hours at 37 ° C., 5% CO ₂ in high humidity. After incubation, the living cells were fixed by the addition of 50% (w / v) trichloroacetic acid (50 µl) and incubated at 4 ° C for 1 hour. The plate was washed three times with excess tap water and air dried.

Cells were stained by adding 0.4% sulforhodamine B (Sigma) solution (100 μl) to the plate and washed 5 times with 1% acetic acid solution (200 μl) to remove excess dye and air dried. The dye was redissolved in 10 mM Tris buffer (200 μl) and the absorbance of each well was read at 565 nm and 690 nm using a BMG Fluorostar microplate reader. Readings at 690 nm were subtracted from readings at 565 nm, and IC ₅₀ values were determined by plotting corrected absorbance values versus compound concentration in the wells (XLfit version 4.0, ID Business Solutions Ltd). These are shown in Table 1 below.

result

The analysis results are shown in Table 1 below.

Claims (16)

Ruthenium (II) compounds of formula (I), or solvates or prodrugs thereof:

In the formula, ^{R 1, R 2, R 3} , R 4, R 5 and R ⁶ is H, C _{1 -7} alkyl, C _{5 -20} aryl, C _{3 -20} heterocyclyl, halo, ester, amido, acyl, sulfo Independently selected from sulfonamido, ether, thioether, azo, amino, or R ¹ and R ² together with the ring to which they are attached contain up to three 3- to 8-membered carbocyclic or heterocyclic rings Forming a saturated or unsaturated carbocyclic or heterocyclic group wherein the carbocyclic or heterocyclic ring can each be fused to one or more other carbocyclic or heterocyclic rings; X is a neutral or negatively charged N- or S-donor ligand; Y is a counter ion; m is 0 or 1; q is 1, 2 or 3; C 'is bonded to two of the A _{1 -12} C alkylene; p is 0 or 1, r is 1 when p is 0, and r is 2 when p is 1; A and B are each independently O-donor, N-donor or S-donor ligand and may be bonded to each other. The compound of claim 1, or a solvate or prodrug thereof, wherein X is selected from azide, isothiocyanate and optionally substituted pyridine ligand. The compound of claim 1, or a solvate or prodrug thereof, wherein X is a thiolate ligand. The compound of claim 1, wherein A and B are together NR ^N4 R ^N5- (CR ^C1 R ^C2 ) _n -NR ^N6 R ^N7 , wherein R ^C1 and R ^C2 are H and C. _1-4 is independently selected from alkyl, R ^N4, R ^N5, R ^N6 and R ^N7 are independently selected from H and C _1-4 alkyl, n is the one that represents the integer of 1 to 4) the compound, or Solvates or prodrugs thereof. The compound of claim 4, or a solvate or prodrug thereof, wherein both R ¹⁴ and R ¹⁵ are hydrogen. The compound of claim 4 or 5, wherein n is 2, or a solvate or prodrug thereof. The compound of any one of claims 4 to 6, wherein R ^N4 , R ^N5 , R ^N6 and R ^N7 are H, or a solvate or prodrug thereof. 8. Saturated or unsaturated carbocyclic or complex according to any one of claims 1 to 7, wherein R ¹ and R ² together with the ring to which they are attached contain a 3- to 8-membered carbocyclic or heterocyclic ring. And a solvate or prodrug thereof, wherein the carbocyclic or heterocyclic ring can each be fused to one or more other carbocyclic or heterocyclic rings. The compound of claim 8, or a solvate or prodrug thereof, wherein R ³ , R ⁴ , R ⁵ and R ⁶ are H. 10. The method according to any one of the preceding ^{claims, R 1, R 2, R} 3, R 4, R 5 and R ⁶ is C _1-7 alkyl, C _{5 -20} aryl, C _{3 -20} heteroaryl A compound selected from cyclyl, halo, ester, amido, acyl, sulfo, sulfonamido, ether, thioether, azo and amino, or solvates or prodrugs thereof. 11. The method of claim 10 ^{wherein, R 1, R 2, R} 3, R 4, R 5 and R ⁶ is A compound, or its solvate or a prodrug thereof to H and C _{1 -7} is independently selected from alkyl. The compound of claim 10 or 11, or a solvate or prodrug thereof, wherein at least four of R ¹ , R ² , R ³ , R ⁴ , R ^5, and R ⁶ are hydrogen. A composition comprising a compound according to any one of claims 1 to 12, or a solvate or prodrug thereof and a pharmaceutically acceptable carrier or diluent. Use of a compound according to any one of claims 1 to 12 or a solvate or prodrug thereof in a method of treatment. Use of a compound according to any one of claims 1 to 12, or a solvate or prodrug thereof, in the manufacture of a medicament for the treatment of cancer.  As a method for treating a subject suffering from cancer, Administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a solvate or prodrug thereof How to include.