WO2014042598A1 - Drug therapy for cancer, including multiple myeloma - Google Patents

Description

DRUG THERAPY FOR CANCER, INCLUDING MULTIPLE MYELOMA

Technical Field

The present invention generally relates to compounds and pharmaceutical compositions for use in drug therapy. Disclosed compounds and pharmaceutical compositions may be used for the treatment of cancer, including a clonal plasma cell malignancy such as multiple myeloma. Background

Human multiple myeloma (MM) is an incurable B cell neoplasm characterized by aberrant expansion of plasma cells within the bone marrow and overproduction of monoclonal immunoglobulin or light-chain proteins. It accounts for 10-15% of haematolog.ical malignancies and 20% of deaths related to cancers of the blood and bone marrow. The median length of survival after diagnosis is approximately 3 years. MM therapy remains challenging. Despite recent therapies, such as Bortezomib, Thalidomide, and Lenalidomide , treatment is limited and palliative. The outcome of patients treated with cytotoxic therapy has not been satisfactory. Therefore, new therapies are needed for relapsed MM.

Bortezomib (Btz) is a therapeutic agent that has been shown to selectively induce apoptosis in malignant cells. Btz is particularly toxic to MM cells, but it has a favorable toxicity profile with most other cell types and was approved by the US Food and Drug Administration in 2003 for the treatment of relapsed refractory disease. Btz is now extensively used in the management of MM and studies have shown that it can extend the median survival of patients with relaped MM by 29.8 months in the Assessment of Proteosome Inhibition for Extending Remission (APEX) trial. However, even after initial response of treatment, nearly all MM patients relapsed or were subsequently refractory to Btz and other treatments. Thus, relapsed and refractory MM is a particularly serious challenge for current anticancer therapies and represents a significant unmet need. Despite the efficacy of Btz for the treatment of MM, the precise mechanism by which Btz kills cancer cells is unknown.

A further problem associated with Btz treatment is that some patients may acquire or possess inherent resistance to Btz treatment. Thus, Btz-resistant MM is a clinically significant problem and is a serious challenge for anticancer therapies.. Furthermore, the mechanism of resistance is poorly understood. A need therefore exists for effective therapies for treating Btz-resistant MM.

Tests using Salubrinal, an elF2a dephosphorylation inhibitor, and Btz have been shown to kill MM cells and leukemic cells. However, the pharmacological properties of Salubrinal, most · notably its poor solubility and low bioavailability, have limited further tests in preclinical trials .

There is therefore a need to provide new drugs and/or drug therapies that overcomes, or at least ameliorates, one or more of the disadvantages described above.

There is a need to provide new drugs and/or drug therapies that treat MM and do not result in the relapse of MM or refractory to treatment.

There is also a need to provide new drugs and/or drug therapies that treat Btz-resistant MM.

There is also a need to provide new drugs and/or drug therapies that exhibit good solubility and bioavailability. Summary- According to a first aspect, there is provided a pharmaceutical composition comprising a first compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

wherein Ri, R₂ , R₃ , R₄ , R5, Re , R7, Rs , R9 and R₁₀ each are independently H; halogen; optionally substituted alkyl, alkenyl , alkynyl, alkoxy, ....amino, sulfinyl, _: sulfonyl, carbonyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato; thiocarbonyl ; thiocyanato; O-carbamyl; N-carbamyl; O- thiocarbamyl ; or N-thiocarbamyl, and a second compound of Formula (IIA), or pharmaceutically acceptable salt thereof:

Formula (IIA)

wherein Rn , R_i2 , R13_/ Ri4_/ and R₁₅ each are independently H; halogen; H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, ' amino, sulfinyl, sulfonyl, carbonyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato; thiocarbonyl ; thiocyanato; O-carbamyl; N-carbamyl; O- thiocarbamyl ; or N-thiocarbamyl .

In a second aspect, there is provided a pharmaceutical composition, comprising a first compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein R_Xj R₂, R3 , R₄ and R₅ each, are independently H or CI and the phenyl group is at least substituted twice, and R₆, R₇, R₈, R9 and R_i0 are H, and a second compound of Formula (IIA), or a pharmaceutically acceptable salt thereof:

Formula (IIA)

wherein R_u, Ri₂, R₁₃, Ri₄ and Ri₅ each are independently H; optionally halogenated, substituted straight chained, branched or cyclic alkyl; alkoxyl; alkenyl; alkynyl; aryl; CO-alkyl; CO-alkenyl; CO-alkynyl; CO-aryl or heteroaryl; CO-alkoxyalkyl ; CO-aryloxyalkyl ; CO- substituted aryl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; or aralkylsulfonyl . Advantageously, a compound of Formula (IA) may synergize with a compound of Formula (IIA) and kill multiple MM cells.

Advantageously, a compound of Formula (IA) in combination with a compound of Formula (IIA) may promote cell stress to induce cytotoxic activity against human multiple myeloma.

Advantageously, a compound of Formula (IA) in combination with a compound of Formula (IIA) reduces the cell viability of MM cells.

Advantageously, a compound of Formula (IA) in combination with a compound of Formula (IIA) may kill more MM cells than a compound of Formula (IA) or a compound of Formula (IIA) alone.

In one embodiment, a compound of Formula (IA) may be

Formula ^' (IB) .

In yet another embodiment, a compound of Formula (IA) may be 2- (2 , 6-dichlorobenzy1idene) hydrazinecarboximidamide (guanabenz) :

Formula (IC) .

In one embodiment, a compound of Formula (IIA) may be [ (1R) -3-methyl-l- ( { (2S) -3-phenyl-2- [ (pyrazin-2- ylcarbonyl) amino] propanoyl}amino) butyl] boronic acid (Bortezomib) : Formula (IIC) .

In a third aspect, there is provided a method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of a first compound of Formula (IA) and a second compound of Formula (IIA) as defined in the first or second aspect. The compounds of Formula (IA) or (IIA) may be in the form of a pharmaceutically acceptable salt or a tautomer thereof.

In a fourth aspect, there is provided a use of a first compound of Formula (IA) and a second compound of Formula (IIA) as defined in the first or second aspect r in the manufacture of a medicament for treating cancer. The compounds of Formula (IA) or (IIA) may be in the form of a pharmaceutically acceptable salt or a tautomer thereof.

Advantageously, the combination of a compound of Formula (IA) and a compound of Formula (IIA) may provide a more effective treatment of cancer, including both animal and human multiple myeloma.

In a fifth aspect, there is provided a method of treating cancer comprising administering to .a patient in need thereof a pharmaceutically effective amount of a compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein Ri , R_{2 /} R₃ , R₄ , R₅ , R6 7 Rs R9 and R_i0 each are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl ; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; methacryloxy; acryloxy; acyloxy; isocyanato; isothiocyanato; sulfinyl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; aralkylsulfonyl ; sulfonamide; thiocarbonyl ; thiocyanato; trihalomethanesulfonamido; O-carbamyl; N- carbamyl; O-thipcarbamyl ; or N-thiocarbamyl .

In a sixth aspect, there is provided a method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein Ri , R₂ , R₃ , R₄ and R₅ each are independently H or CI and the phenyl group is at least substituted twice, and R₆ , R₇ , R₈ , R₉ and R₁₀ are H.

- In one embodiment, a compound of Formula (IA) may be

2- (2 , 6-dichlorobenzylidene) hydrazinecarboximidamide (Guanabenz) , pharmaceutically acceptable thereof :

Formula (IC) .

advantageously discovered that the ability of a compound of Formula (IA) , as defined in the fifth, or sixth aspect, to kill MM cells may not depend on its a2 adrenergic receptor binding activity, but is mediated by a distinct cellular target, GADD34, a critical component of the stress-induced eIF2a phosphatase. In one embodiment, a compound of Formula (IA) may be Guanabenz.

Advantageously, a compound of Formula (IA) as defined in the fifth or sixth aspect may kill multiple MM cells.

Advantageously, a compound of Formula (IA) as defined in the fifth or sixth aspect may promote cell stress to induce cytotoxic activity against human multiple myeloma which is mediated by the cell target, GADD34.

Advantageously, a compound of Formula (IA) as defined in the fifth or sixth aspect may reduce cell viability of MM cells.

Further advantageously, a compound of Formula (IA) as defined in the fifth or sixth aspect may kill multiple MM cells which are resistant to Btz treatment.

Advantageously, a compound of Formula (IA) as defined in the fifth or sixth aspect may reduce cell viability of Btz -resistant MM cells.

Definitions

Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid^' chemistry, described herein, are those well-known and commonly used in the art.

The following are some definitions that may be helpful in understanding the description of the present invention. These are intended as general definitions and should in no way limit the scope of the present invention to those terms alone, but are put forth for a better understanding of the following description.

Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements.

As used herein, unless otherwise specified, the following terms have the following meanings, and unless otherwise specified, the definitions of each term (i.e. moiety or substituent) apply when that term is used individually or as a component of another term (e.g., the definition of aryl is the same for aryl and for the aryl portion of arylalkyl, alkylaryl, arylalkynyl, and the like) .

As used herein, the term "alkyl" includes within its meaning monovalent ("alkyl") and divalent ("alkylene") straight chain or branched chain saturated aliphatic groups having from 1 to 12 carbon atoms, eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,.or 12 carbon atoms. For example, the term alkyl includes, but is not limited to, methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2 -butyl, isobutyl, tert- butyl, amyl, 1 , 2-dimethylpropyl , 1, 1-dimethylpropyl, pentyl, isopentyl, hexyl, -methylpentyl , 1-methylpentyl , 2-methylpentyl, 3 -methylpentyl , 2 , 2 -dimethylbutyl , 3,3- dimethylbutyl , 1 , 2 -dimethylbutyl , 1 , 3 -dimethylbutyl ,

1, 2, 2-trimethylpropyl, 1 , 1 , 2 -trimethylpropyl , 2- ethylpentyl, 3 -ethylpentyl , heptyl, 1-methylhexyl , 2,2- dimethylpentyl , 3 , 3 -dimethylpentyl , , 4 -dimethylpentyl , 1, 2-dimethylpentyl, 1 , 3 -dimethylpentyl , 1,4- dimethylpentyl, 1 , 2 , 3-trimethylbutyl , 1,1,2- trimethylbutyl, 1, 1, 3 -trimethylbutyl, 5 -methylheptyl , 1- methylheptyl, octyl , nonyl, decyl, undecyl, dodecyl and the like. Alkyl groups may be optionally substituted.

As used herein, the term "alkenyl" refers to divalent straight chain or branched chain unsaturated aliphatic groups containing at least, one carbon-carbon double bond and having from 2 to 12 carbon atoms, eg, 2, 3, 4, 5,_; 6,

7, 8, 9, 10, 11 or 12 carbon atoms. For example, the term alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 1-butenyl, 2-butenyl, 2 -methylpropenyl , 1-pentenyl, 2-pentenyl, 2-methylbut-l-enyl, 3 -methylbut- 1- enyl, 2 -methylbut-2 -enyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2 , 2-dimethyl-2-butenyl, 2-methyl-2-hexenyl, 3-methyl-l- pentenyl, 1 , 5-hexadienyl , heptenyl, octenyl, nonenyl and decenyl and the like. Alkenyl groups may be optionally substituted.

As used herein, the term "alkynyl" refers to trivalent straight chain or branched chain unsaturated aliphatic groups containing at least one carbon-carbon triple bond and having from 2 to 6 carbon atoms, eg, 2, 3, 4, 5, 6, 7,

8, 9, 10, 11 or 12carbon atoms. For example, the term alkynyl includes, but is not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 3 -methyl-1-pentynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Alkynyl groups may be optionally substituted. The term "alkoxy" or variants such as "alkoxide" as used herein refers to an -O-alkyl radical. Representative examples include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, and the like.

The term "amino" includes an amine group (i.e., -NH₂) or a substituted amine group.

The- term "amido" or variants such as "amide" as .used herein refers to moieties including a carbon atom double bonded to an oxygen atom and single bonded to an amino moiety.

As used herein, the term "carbonyl" refers to a divalent group of formula —(CO)—. Carbonyl groups may be substituted with, for example, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxyalkyl, aryloxyalkyl or substituted aryl and the like.

As used herein, the term "carbamyl" refers to a group of formula -OC(=0)-N-. The term "O-carbamyl" refers to a carbamyl group attached via the 0 atom. The term "N- carbamyl" refers to a carbamyl group attached via the N atom.

As used herein, the term "cyano" refers to a group of formula —CN.

The term "carbocycle" , . or variants such as "carbocycli^'c ring" as used herein, includes within its meaning any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7 , 8 , 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. The term "carbocycle" includes within its meaning cycloalkyl, cycloalkenyl and aryl groups. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,

[3.3.0] bicyclooctane, [4.3.0] bicyclononane ,

[4. .0] bicyclodecane (decalin) , [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin) . Preferred carbocycles > unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, and indanyl. Carbocycles may be optionally substituted. -

The term "cycloalkyl" as used herein refers to a non- aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non- limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include I - decalinyl, norbornyl, adamantyl and the like. Further non- limiting examples of cycloalkyl include the following:

The term "cycloalkenyl" as used herein refers to a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, which contains at least one carbon-carbon double bond. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1, 3-dienyl, and the like. Non- limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl, as well as unsaturated, moieties of the examples shown above for cycloalkyl. Cycloalkenyl groups may be optionally substituted.

The term "aryl", or variants such as ^' "aromatic group" or "arylene" as used herein refers to monovalent ("aryl") and divalent ("arylene") single, po yriuclear, conjugated or fused residues of aromatic hydrocarbons having from 6 to 10 carbon atoms. Such groups include, for example, phenyl, biphenyl, naphthyl, phenanthrenyl , and the like. Aryl groups may be optionally substituted.

The term "halogen", or variants such as "halide" or

"halo" as used herein, includes within its meaning fluorine, chlorine, bromine and iodine.

The term "heteroaryl" as used herein refers to an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5^' to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. "Heteroaryl" may also include a heteroaryl as defined above fused to an aryl as defined above. Non- limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N- substituted pyridones) , isoxazolyl, isothiazolyl , oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 , 2 , 4 -thiadiazolyl , pyrazinyl, pyridazinyl, quinoxalinyl , phthalazinyl , oxindolyl, imidazo[l , 2 -alpyridinyl , imidazo[2,l b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl , benzothienyl , quinolinyl, imidazolyl, thienopyridyl , quinazolinyl , thienopyrimidyl , pyrrolopyridyl, imidazopyridyl , isoguinolinyl , benzoazaindolyl, 1 , 2 , 4 - triazinyl , benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. Heteroaryl groups may be optionally substituted.

The term "heterocycle" as used herein refers to a group comprising a covalently closed ring herein at least one atom forming the ring is a carbon atom and at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms, any of which may be saturated, partially unsaturated, or aromatic. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms) . Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g., C1-C6 heterocycle), at least one other atom (the heteroatom) must be present in the ring. Designations such as "C1-C6 heterocycle" refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. It is understood that the heterocylic ring will have additional heteroatoms in the ring. In heterocycles comprising two or more heteroatoms , those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. Examples of heterocycles include heterocycloalkyls (where the ring contains fully saturated bonds) and heterocycloalkenyls (where the ring contains one or more unsaturated bonds) such as, but are not limited to the following:

wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another.

As used herein, the term "hydroxy" refers to a group of formula -OH.

^•As used herein, the -term "isocyanato"' refers to a group of formula —NGO.

As used herein, the term "isothiocyanato" refers to a -NCS group.

As used herein, the term "trimethylsilyl". refers to a trimethyl-substituted Si group (i.e., -SiR₃, wherein R is methyl) . ,

As used herein the_. term "silyl ether" refers to a silicon atom bonded to one or more . carbon-containing groups via an oxygen atom (i.e., an ether linkage) .

. . As used herein, the term "sulfinyl" refers to refers to a group "-S(0)-R" wherein R may be. selected from, for example, H, alkyl, alkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl , amino or amide .

As used herein, the term "sulfonyl" refers to group "- S0₂-R" wherein R may be selected from, for example, H, alkyl, alkenyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl , amino · or amide .

As used herein, the term "thiocarbonyl" refers to a group —C ( S)— .

As used herein, the term "thiocyanato" refers to a group -SCN.

As used herein, the term "thiocarbamyl" refers to a group . of formula -0C(=S)NH-. The term "N-thiocarbamyl" refers to a^" thiocarbamyl attached via the N atom. The term "0- thiocarbamyl" refers to a thiocarbamyl attached via the O atom.

The term "optionally substituted" as used herein means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups other than hydrogen provided that the indicated atom' s normal valency is not exceeded, and that the substitution results in a stable compound. Such groups may be, for example, halogen, hydroxy, oxo, cyano, nitro, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl4alkoxy, alkylthio, hydroxyalkyl , alkoxyalkyl, cycloalkyl, cycloalkylalkoxy, alkanoyl, alkoxycarbonyl , alkylsulfonyl , alkylsulfonyloxy, alkylsulfonylalkyl , arylsulfonyl , arylsulfonyloxy, arylsulfonylalkyl , alkylsulfonamido, alkylamido, alkylsulfonamidoalkyl , alkylamidoalkyl,, arylsulfonamido, arylcarboxamido, arylsulfonamidoalkyl , arylcarboxamidoalkyl , aroyl, aroyl4alkyl, arylalkanoyl , acyl, aryl, aryla_.lkyl, alkylaminoalkyl , a group R^XR^YN- , R^xOCO (CH₂ ) _m, RC0N (R^Y) ( CH₂ ) _m, R^xR^YNCO (CH₂ ) _m, R^xR^yNS0₂ ( CH₂ ) _m or R^xS0₂NR^Y (CH₂) _m (where each of R and ^■ R^y is independently selected from hydrogen or alkyl , or where appropriate RR^y forms part of carbocylic or heterocyclic ring and m is 0, 1 , 2, 3 or 4), a group R^xR^yN(CH₂)_p- or R¾¾ (CH₂) _pO- (wherein p is 1 , 2, 3 or 4); wherein when the substituent is R^xR^yN(CH₂)_p- or R^xR^yN (CH₂) _p0, R^x with at least one^' CH₂ of the (CH₂)_P portion of the group may also form a carbocyclyl or heterocyclyl group and R^Y may be hydrogen, alkyl.

The term "substituted" as used herein means, the group to which this term refers is substituted with one or more groups other than hydrogen provided that the indicated atom' s normal valency is not exceeded, and that the substitution results in a stable compound. Such- groups may be, for example, halogen, hydroxy, oxo, cyano, nitro, alkyl,. alkoxy, haloalkyl, haloalkoxy, aryl4alkoxy, alkylthio, hydroxyalkyl , alkoxyalkyl, cycloalkyl, cycloalkylalkoxy, alkanoyl, alkoxycarbonyl , alkylsulfonyl , alkylsulfonyloxy, alkylsulfonylalkyl , arylsulfonyl , arylsulfonyloxy, ^" arylsulfonylalkyl , alkylsulfonamido, alkylamido, alkylsulfonamidoalkyl , alkylamidoalkyl , arylsulfonamido, arylcarboxamido, arylsulfonamidoalkyl , arylcarboxamidoalkyl, aroyl , aroyl4alkyl, arylalkanoyl , acyl, aryl, arylalkyl, alkylaminoalkyl , a group R^XR^YN- , R^xOCO(CH₂j_m, R^xCON(R^y) (CH₂) _m, R^xR^yNCO (CH₂) _m, R^xR^yNS0₂ (CH₂ ) _m or RS0₂NR^Y (CH₂) _m (where each of R^x and R^y is independently selected from hydrogen or alkyl , or where appropriate R^xR^y forms part of carbocylic or heterocyclic ring and m is 0, 1 , 2, 3 or 4), a group R^xR^yN(CH₂)_p- or R^XR^YN (CH₂) _pO- (wherein p is 1 , 2, 3 or 4) ;. wherein when the substituent is R^xR^yN(CH₂) _p- or ^' R^xR^yN (CH₂) _pO, R^x with at least one CH₂ of the (CH₂)_p portion of the group may also form a carbocyclyl or heterocyclyl group and R^Y may be hydrogen, alkyl.

The term "pharmaceutically acceptable salt" includes, for example, the hydrochloride, hydrobromide , hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, and tartrate salts. The term "pharmaceutically acceptable carrier" is intended to. include solvents, dispersion media, coatings, anti-bacterial and anti-fungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compound, use thereof in the therapeutic compositions and methods of treatment and prophylaxis is contemplated. Supplementary active compounds may also be incorporated into the compositions according to the present invention. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. "Dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the individual to be treated; each unit containing a predetermined quantity of compound (s) is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The compound (s) may be formulated for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in an acceptable dosage unit . In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

The word "substantially" does not exclude "completely" e.g. a. composition which is "substantially free"^' from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.

As used herein, the term "about", in the context of concentrations of components of the formulations, typically means +/- 5% of the stated value, more typically +/-. 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1% of the stated value, and even more typically +/- 0.5% of the stated value.

In the context of this specification, the term

"treatment" refers to any and all uses which remedy a disease state or symptoms, prevent the establishment of disease, or otherwise prevent, hinder, retard, or reverse the progression of disease or other undesirable symptoms in any way whatsoever.

In the context of this specification the terms "therapeutically effective amount" and "diagnostically effective amount", include within their meaning a sufficient but non-toxic amount of a compound or composition of the invention to provide the desired therapeutic or diagnostic effect. The exact amount required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, the severity of the condition being treated, the particular agent being administered, the mode of administration, and so forth. Thus, it is not possible to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" may be determined^' by one of ordinary skill in the art using only routine experimentation.

In the context of this invention the term "administering" and . variations of that . term including "administer" and "administration", includes contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means .

Throughout this specification, unless the context reguires otherwise, the. word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of , a stated step or element or integer or group of steps or elements or integers, but not to the exclusion of any other step or element or integer or group of elements or integers. Thus, in the context of this specification, the term "comprising" means "including peripherally, but not necessarily solely".

When describing the compounds, compositions, methods and processes of the invention, the following terms have the following meanings unless otherwise indicated. Additionally, as used herein, the singular forms "a, " "an" and "the" include the corresponding plural forms unless the context of use clearly . dictates otherwise.

Certain embodiments may also be described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the embodiments with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

Throughout this disclosure, certain embodiments may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on · the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3 , from 1 to , from 1 to 5, from 2 to 4 , from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features .

Detailed Disclosure of Embodiments

Exemplary, non-limiting -embodiments of the disclosed pharmaceutical composition will now be disclosed.

There is provided in a fist aspect, a pharmaceutical composition comprising a first compound of Formula (IA) or a harmaceutically acceptable salt or tautomer thereof:

Formula (IA)

wherein R₁₍ R₂, R₃, R₄, R_5/ R₆, R₇, R₈, R₉ and R_:oeach are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl , alkoxy, amino, sulfinyl, sulfonyl, carbonyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato; thiocarbonyl ; thiocyanato ; O-carbamyl; N-carbamyl; O- thiocarbamyl ; or N-thiocarbamyl , and a second compound of Formula (IIA) or a harmaceutically acceptable salt thereof:

Formula (IIA)

wherein Ru , Ri₂ , R13, Ri4 and R₁₅ each are independently H ; halogen; H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, sulfinyl, sulfonyl, carbonyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic^' acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato ; thiocarbonyl; thiocyanato; O-carbamyl; N-carbamyl; O- thiocarbamyl ; or N-thiocarbamyl .

A pharmaceutical composition comprising a compound of

Formula (IA) and a compound of Formula (IIA) may be used to kill multiple MM cells and may be an effective treatment of human multiple myeloma.

A pharmaceutical composition comprising a compound of ^"Formula (IA) and a compound of Formula (IIA) may work synergistically with each other to kill MM cells and may be an effective treatment of human multiple myeloma.

In a second aspect, there is also provided a pharmaceutical composition comprising a first compound of

Formula (IA) or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein Ri, R₂, R₃, R₄ and R₅ each are independently H or Cl and the phenyl group is at least substituted twice, and R₆, R₇, Re# R9 and R₁₀ are H, and a second compound of Formula (IIA) or a pha

wherein Rn, R₁₂, Ri_3/ Ri₄, and R_i5 eac are independently H; optionally halogenated, substituted straight chained, branched or cyclic alkyl; alkoxyl; alkenyl; alkynyl; aryl; CO-alkyl; CO-alkenyl; CO-alkynyl; CO-aryl or heteroaryl; CO-alkoxyalkyl ; . CO-aryloxyalkyl ; CO-substituted aryl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; or aralkylsulfonyl .

In a compound of Formula (IA) , Ri, R₂, R₃, R₄, R₅, R₆,

R₇, R₈, R₉ and Ri₀ may be selected from H; halogen optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl. Ri, R₂, R₃, R₄, -5, Re, R7, Rs, R9 and R_xo may be selected from H. Ri, R , R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R_i0 may be selected from optionally substituted alkyl selected from optionally substituted straight chain or branched chain methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl . Ri, R₂, R₃, R₄, R_5/ R₆ , R₇ , R₈ , R9 and Ri₀ may be selected from optionally substituted alkenyl selected from optionally substituted ethenyl, propenyl, butenyl, 1-butenyl, 2 -butenyl, 2- methylpropenyl, 1-pentenyl, 2-pentenyl, 2-methylbut-l- enyl, 3 -methylbut-1-eny1 , 2 -methylbut-2 -enyl , 1-hexenyl, 2-hexenyl, 3-hexenyl, 2 , 2 -dimethyl-2 -butenyl , 2-methyl-2- hexenyl, 3 -methyl-1-pentenyl, 1, 5-hexadienyl, heptenyl, octenyl , nonenyl or decenyl . R_{l f} R₂ , R₃ , R₄ , R₅ > R₆ , R7, Rs , R₉ and Rio may be selected from optionally substituted alkynyl selected from optionally substituted ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 3 -methyl-1-pentynyl heptynyl, octynyl, nonynyl or decynyl. R_{l f} R₂ , R3, R₄ , R₅ , R₆ , R₇ , R₈ , R₉ and Ri₀ may be selected from optionally substituted aryl selected from optionally substituted phenyl, biphenyl, naphthyl or phenanthrenyl . R_{i (} R₂ , R₃ , R₄ , R₅ , R₆ , R7, -Re-, R9 and Rio roay be selected from optionally substituted heteroaryl selected from optionally substituted pyrroline, pyrrolidine, imidazoline, imidazolidihe, pyrazoline, pyrazolidine, pyrane, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran.

Three -of Ri, R₂ , R₃ , "R₄ , R₅ may be selected from chlorine and the others may be selected from H.

Two of Ri, R₂ , R₃ , R₄ , R₅ may be selected from chlorine and the others may be selected from H.

A compound of formula (IA) may be a compound of formula (IB) :

A compound of ^' formula (IA) may be a compound of formula (IC) , 2- (2 , 6-dichlorobenzylidene) h drazinecarboximidamide (Guanabenz) :

In a compound of Formula (IIA) , R₁₁₍ R₁₂, Ri₃, Ri₄ and R₁₅ may be selected from H; halogen; optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl. R_U| R₁₂, Ri₃, R_i4 and Ri5 may be selected from H. Rn, R₁₂, Ri₃, R_i4 and Ri₅ may be selected from optionally substituted alkyl, selected from optionally substituted straight chain or branched chain methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl , decyl , undecyl or dodecyl. Rn, R₁₂, R^'i₃ , R_i4 and Ri5 may be selected from optionally substituted alkenyl selected from optionally substituted ethenyl, propenyl, butenyl, 1-butenyl, 2-butenyl, 2 -methylpropenyl , 1- pentenyl, 2-pentenyl, 2 -methylbut- 1-enyl , 3 -methylbut- 1- enyl, 2 -methylbut-2-enyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2 , 2-dimethyl-2-butenyl, ^" 2 -methyl-2-hexenyl, 3-methyl-l- pentenyl, 1, 5-hexadienyl, heptenyl, octenyl, nonenyl or decenyl. R₁₍ R₂, R₃ , R₄, R₅, R₆, R7_/ Rs/ R₉ and R₁₀ may be selected from optionally substituted alkynyl selected from optionally substituted ethynyl, propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 3 -methyl-1-pentynyl , heptynyl, octynyl, nonynyl or decynyl. R_i( R₂, R₃, R₄, R5 R7/ Rs R₉ and R_i0 may be selected from optionally substituted aryl selected from optionally substituted phenyl, biphenyl, naphthyl or phenanthrenyl . Ri, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R_i0 may be selected from optionally substituted heteroaryl selected from optionally substituted pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazolone, pyrazolidine , pyrane, piperidine, morpholine, thiomorpholine, piperazine or hydrofuran.

A compound of formula (IIA) may be a compound of Formula (IIB) : " -

In a compound of Formula (IIB) , Rix , R_i2 , R₁₃ , Ri₄ and R_i5 may be selected from H; halogen; optionally substituted alkyl, alkenyl, alkynyl, aryl, heteroaryl . R_u, R₁₂ , R₁₃, Ri₄ and Ri₅ may be selected from H. R_u, R₁₂ , R₁₃, R_w and ¾₅ may be selected from optionally substituted alkyl, selected from optionally substituted straight chain or branched chain methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl . Ru , Ri₂ , R₁₃, 14 and R₁₅ may be selected, from optionally substituted alkenyl selected from optionally - substituted ethenyl, propehyl^ butenyl, 1-butenyl, 2-butenyl, .2-methylpropenyl, 1- pentenyl, 2-pentenyl, 2 -methylbut- 1-enyl , 3 -methylbut- 1- enyl, 2 -methylbut-2-enyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2 , 2-dimethyl-2 -butenyl, 2 -methyl-2 -hexenyl , 3-methyl-l- pentenyl, 1, 5-hexadienyl, heptenyl, octenyl, nonenyl or decenyl. Ru , R_{i2 /} Ri₃ R1 and R₁₅ may be selected from optionally substituted alkynyl selected from optionally substituted ethynyl, propynyl, 1-butynyl, 2-butynyl, 1- pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 3- methyl-l-pentynyl, heptynyl, octynyl, nonynyl or decynyl . R11 , R-12_/ Ri3i R-14 and Ri₅ may be selected from optionally substituted aryl selected from optionally substituted phenyl, biphenyl, naphthyl or phenanthrenyl . R_n, Ri₂, R13, R₁₄ and R₁₅ may be selected from optionally substituted heteroaryl selected from optionally substituted pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyrane, piperidine, morpholine, thiomorpholine , piperazine or hydrofuran.

A compound of Formula (IIA) or Formula (IIB) may be a compound of Formula (IIC) [ (1R) -3-methyl-l- ( { (2S) -3- phenyl-2- [ (pyrazin-2-ylcarbonyl)

amino] proparioyi} amino) butyl] boronic acid (Bortezomib) :

in a third aspect, there is also provided a method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of a first compound of Formula (IA) and a second compound of Formula (IIA) as "-disclosed.

The method of _. the third aspect may comprise administering disclosed compounds of Formula (IB) and Formula (IIA) ; compounds of Formula (IC) and Formula (IIA) ; compounds of Formula (IA) and Formula (IIB) ; compounds of Formula (IB) and Formula (IIB); compounds of_. Formula (IC) and Formula (IIB) ; compounds of Formula (IA) and Formula (IIC) ; compounds of Formula (IB) and Formula (IIC) ; or compounds of Formula (IC) and Formula (IIC) . The compounds of Formula (IA) , (IB), (IC) , (IIA), (IIB) and (IIC) in the method of the third aspect may be in the form of a pharmaceutically acceptable salt or a tautomer thereof . In a fourth aspect, there is also provided the use of a first compound of Formula (IA) and a second compound of Formula (IIA) in the manufacture of a medicament in the manufacture of a medicament for treating cancer. The use of the fourth aspect may comprise compounds of Formula (IB) and Formula (IIA) ; compounds of Formula (IC) and Formula (IIA) ; compounds of Formula (IA) and Formula (IIB) ; compounds of Formula (IB) and Formula (IIB) ; compounds of Formula (IC) and Formula (IIB) ; compounds of Formula (IA) and Formula (IIC); compounds of Formula (IB) and Formula (IIC) ; or compounds of Formula (IC) and Formula (IIC). The compounds of Formula (IA) , (IB), (IC) , (IIA), (IIB) and (IIC) in the use of the fourth aspect may be in the form of a pharmaceutically acceptable salt or a tautomer thereof.

The pharmaceutically acceptable salt of a compound of Formulas (IA) , (IB) , . (IC) , (IIA), (IIB) or (lie) according to any one of the first to fourth aspects may be a hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate^", lactate, maleate, malate, succinate, or tartrate salt. The pharmaceutically acceptable salt may be an acetate salt.

The administration of a pharmaceutically effective amount of a first compound of Formula (IA) and a second compound of Formula (IIA) according to the third aspect may be via oral administration, parenteral administration, intravenous administration or topical administration.

The disclosed first compound and disclosed second compound may be administered together or separately. The compounds may be administered at least once, at least twice, or at least three times a day.

The method of treating cancer according to the third aspect may further comprise administering at least one of (RS) -2- (2 , 6-dioxopiperidin-3-yl) -lH-isoindole-1, 3 (2H) - dione (Thalidomide), (RS) -3- (4-amino-l-oxo-3H-isoindol-2- yl) piperidine-2 , 6-dione (Lenalidomide) , or (RS) -N,N-bis (2- chloroethyl) -1 , 3 , 2-oxazaphosphinan-2-amine 2-oxide (Cyclophosphamide) .

The combination of a disclosed compound of Formula (IA) with a disclosed compound of Formula (IA) and may synergistically kill multiple myeloma cells and thereby provide a more effective treatment of MM. The disclosed synergistic combination may promote cell stress to induce cytotoxic activity against human multiple myeloma and reduce the cell viability of MM cells. The disclosed synergistic combination may kill more MM cells than a compound of Formula (IA) or a compound of Formula (IIA) alone and may provide a more effective treatment o cancer, including both animal and human multiple myeloma. The synergistic combination may comprise Guanabenz and Bortezomib.

In a fifth aspect, there is provided a method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of a disclosed compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof.

In one embodiment, Formula (IA). of the fifth aspect ma

Formula (IA)

wherein R₁₍ R_2/ R₃ , R₄ and R₅ each are independently H or CI and the phenyl group is at least substituted twice, and R₆, R₇, R₈, R₉ and R₁₀ are H. In another embodiment, Formula (IA) of the fifth aspect may be :

rmula (IB)

or a pharmaceutically acceptable salt or tautomer thereof.

In a^' further embodiment, Formula (IA) of the fifth aspect may be 2- (2 , 6-dichlorobenzylidene) hydrazinecarboximidamide (Guanabenz) of Formula (IC) :

Formula ( IC)

or a pharmaceutically acceptable salt or tautomer thereof.

In a sixth aspect, there is provided the use of a disclosed compound of Formula (IA) in the manufacture of a medicament for treating cancer.

The administration of a pharmaceutically effective amount of a first compound of Formula (IA) and a second compound of Formula (IIA) according to the fifth aspect may be via oral administration, parenteral administration, intravenous administration or topical administration.

The disclosed compound of formula (IA) may be administered at least once.,- at least twice, or at least three times a day.

The method of treating cancer according to the fifth aspect may further comprise administering at least one of

(RS) -2- (2, 6-dioxopiperidin-3-yl) -lH-isoindole-1 , 3 (2H) - dione (Thalidomide), (RS) -3- (4-amino-l-oxo-3H-isoindol-2- yl) iperidine-2 , 6-dione (Lenalidomide) , or (RS) -N, -bis (2- chloroethyl) -1, 3 , 2 -oxazaphosphinan-2 -amine 2 -oxide

(Cyclophosphamide) .

The pharmaceutically acceptable salt of a compound of Formulas (IA) , (IB) or (IC) according to any one of the fifth or sixth aspects may be a hydrochloride, hydrobromide , hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, or tartrate salt. The pharmaceutically acceptable salt may be an acetate salt.

The ability of a compound of Formula (IA) as defined in the fifth or sixth aspect to kill MM cells may not depend on its a2 adrenergic receptor binding activity, but may be mediated by a distinct cellular target, GADD34, a critical component of the stress-induced eIF2 phosphatase. A compound of Formula (IA) as defined in the fifth or sixth aspect may kill multiple MM cells. The compound of Formula (IA) may promote cell stress to induce cytotoxic activity against human multiple myeloma which is mediated by cell target, GADD34 and reduce cell viability of MM cells.

A compound of Formula (IA) as defined in the fifth or sixth aspect may further kill multiple MM cells which are resistant to Btz treatment. A compound of Formula (IA) may reduce the cell viability of Btz-resistant MM cells.

The cancer of any one of the third to sixth aspects may be a clonal plasma cell malignancy, or animal or human multiple myeloma. The cancer may be Btz-resistant cancer, such as Btz-resistant clonal plasma cell malignancy or Btz-resistant animal or human multiple myeloma. The cancer may be relapsed or refractory animal or human multiple myeloma. Brief Description Of Drawings

The accompanying drawings illustrate a disclosed embodiment and serves to explain the principles of the disclosed embodiment. It is to be understood, however, that the drawings are designed for purposes of illustration only, and not as a definition of the limits of the invention.

Fig. 1 shows the killing effect that a combination of Guanabenz (GBZ) and Bortezomib (BTZ) have on MM cells. p<0.001. Data based on three independent replicates.

Fig. 2 shows the killing effect GBZ has on MM cells which are resistant to BTZ. P<0.001. Data based on three independent replicates. Fig. 3 shows the effect that administration of GBZ has on sizes of tumors in nude mice.

Fig. 4 shows the toxicity of GBZ on primary patient - derived MM cells. Examples

Non-limiting examples of the invention and a comparative example will be further described in greater detail by reference to specific Examples, whioh should no be construed as in any way limiting the scope of the invention.

Example 1: Synergism between Guanabenz (GBZ) (Trade name Wytensin, Guanabenz acetate purchased from Sigma-Aldrich) and Bortezomib (BTZ) (Originally codenamed PS-341, marketed as Velcade by Millenium Pharmaceuticals and

Bortecad by Cadila Healthcare. BTZ was from LC Laboratories used for laboratory testing) . As shown in Fig. 1, the combination of GBZ and BTZ kills more cells than using either GBZ or BTZ alone. While BTZ and GBZ both displayed decreased cell viability upon exposing each of them to U266 cells, the combination of GBZ and BTZ displayed enhanced killing of cells and a reduced cell viability of U266 cells at about 50%.

Example 2: GBZ kills BTZ-resistant MM cells

As shown in Fig. 2, GBZ alone is able to kill MM cells, which are resistant to BTZ treatment. Fig. 2 shows that GBZ reduced cell viability of BTZ-resistant MM cells, but not BTZ. This is very important because there is significant recurrence of MM observed in BTZ-treated patients. Despite the initial benefits of BTZ treatment, almost all MM patients eventually relapse or became refractory to existing treatments. Therefore, the finding that GBZ kills MM cells which are insensitive to BTZ suggests that GBZ could be used as an alternative drug for. relapsed or refractory MM patients.

Example 3: Preclinical (animal) studies

Animal studies using a tumor xenograft model in immunocompromised nude mice were done to evaluate the efficacy of GBZ to reduce the tumor burden.

MM cells were injected into the flank of nude mice till visible or palpable tumours were obtained. Once the presence of a tumor of defined size was established, the groups of animals were administered with GBZ via an intraperitoneal injection and continued growth of tumor monitored.

As shown in Fig. 3, GBZ, like BTZ (an FDA approved drug for treatment of MM), significantly inhibited tumdr growth in this widely utilised mouse tumor model. Fig. 3 shows that the administration of GBZ reduced the tumor growth in mice .

Example 4: Analysis of Patient -derived MM cells

Primary tumor cells from five patients were analysed in vitro for their sensitivity to GBZ-induced cell death. These studies have established that 3 out of 5 of the patient-derived cells displayed reduced cell viability following short-term exposure with GBZ. Specifically, in cells from one patient, the administration of GBZ reduced cell viability to around 50% when treated for 24hr (Fig. 4) . These studies also highlighted the existence of a subset of human MM tumours that may be resistant to GBZ. Applications

The disclosed pharmaceutical composition comprising an above mentioned, compound of Formula (IA) and a compound of Formula , (IIA) may be used as an effective treatment of cancer including a clonal plasma cell malignancy, for example, animal or human multiple myeloma.

The disclosed pharmaceutical composition comprising an above mentioned compound of Formula (IA) and a compound of Formula (IIA) may also be used in the manufacture of a medicament for treating cancer including a clonal plasma cell malignancy, for example, animal or human multiple myeloma .

The above mentioned compound of Formula (IA) and a compound of Formula (IIA) may also be administered in a method of treating cancer including a clonal plasma cell malignancy, for example, animal or human multiple myeloma.

The disclosed pharmaceutical compositions comprising a compound of Formula (IA) and a compound of Formula (IIA) may exhibit good solubility and bioavailability. The disclosed pharmaceutical compositions may be used as an effective treatment of relapsed or refractory multiple myeloma.

The disclosed pharmaceutical compositions comprising a compound of Formula (IA) and a compound of Formula (IIA) may treat animal or human multiple myeloma and may not result in a relapse or refractory to treatment .

The disclosed pharmaceutical compositions comprising a compound of Formula (IA) and a compound of Formula (IIA) may be further used i pharmaceutical industries as it may possess biological characteristics such as being anti-cancer.

A disclosed compound of Formula (IA) may be used as an effective treatment of cancer including a clonal plasma cell malignancy, for example, animal or human multiple myeloma.

The disclosed compound of Formula (IA) may also be used in the manufacture of a medicament for treating cancer including a clonal plasma cell malignancy, for example , animal or human multiple myeloma.

The disclosed compound of Formula (IA) may be used to treat Btz-resistant cancer, such as Btz-resistant multiple myeloma.

The disclosed compound of Formula (IA) may be used to treat relapsed or refractory multiple myeloma.

It will be apparent that various other modifications and adaptations of the invention will be apparent to the person skilled in the art after reading the foregoing disclosure without departing from the spirit and scope of the invention and it is intended that all such modifications and adaptations come within the scope of the appended claims.

Claims

Claims

A pharmaceutical composition comprising a first compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

¾/ R9

and Ri₀each are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, sulfinyl, sulfonyl, carbonyl , aryl, heteroaryl , carbocyclyl, or heterocyclyl ; hydroxy1 ; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; ¹ silylether; isocyanato; isothiocyanato; thiocarbonyl ; thiocyanato; O-carbamyl; N-carbamyl; 0-thiocarbamyl ; or N-thiocarbamyl , and a second compound of Formula (IIA) or a pharmaceutically acceptable salt thereof:

wherein RH, R_i2, R13_/ 14V and Ri₅ each are independently H; halogen; H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, sulfinyl, sulfonyl, carbonyl, aryl , heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato; thiocarbonyl ; thiocyanato; O-carbamyl; N-carbamyl; O- thiocarbamyl ; or N-thiocarbamyl.

The pharmaceutical composition of claim 1, wherein the first compound is of Formula (IA) , or a table salt or tautomer

Formula (IA)

wherein R_{1 (} ¾ , Rj , R₄ and R₅ each are independently H or CI and the phenyl group is at least substituted twice , and

R₆ , R₇ , R₈ , R₉ and R₁₀ are H, and the second compound is of Formula (HA) , or a pharmaceutically acceptable salt thereof:

Formula (IIA)

wherein R_n , R₁₂ , Ri₃ , i₄, and R₁₅ each are independently H; optionally halogenated, substituted straight chained, branched or cyclic alkyl; alkoxyl; alkenyl; alkynyl; aryl; CO-alkyl;. CO-alkenyl; CO- alkynyl; CO-aryl or heteroaryl ; CO-alkoxyalkyl ; CO- aryloxyalkyl ; CO-substituted aryl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; or aralkylsulfonyl .

The pharmaceutical composition of any one of claims 1 or 2, wherein the first compound is of Formula (IB):

Formula (IB)

or a pharmaceutically acceptable salt or tautomer thereof .

The pharmaceutical composition_. of any one of claims 1 or 2, wherein the first compound is of Formula

(

Formula (IC)

or a pharmaceutically acceptable salt or tautomer thereof.

The pharmaceutical composition of any one of claims 1-2 and 4, wherein the first compound is 2- (2,6- dichlorobenzylidene) hydrazinecarboximxdamide

(Guanabenz) , or a pharmaceutical acceptable salt thereof . The pharmaceutical composition of any one of the preceding claims, wherein the second compound is of

Formula (IIB) , or a pharmaceutically acceptable salt thereof :

Formula (IIB)

wherein at least one of Ru to Ri₅ is hydrogen. 7. The pharmaceutical composition of claim 6, wherein the second compound is [ (1R) -3 -methyl-1- ( { (2S) -3 - phenyl-2- [ (pyrazin-2- ylcarbonyl) amino] propanoyl} amino) butyl] boronic acid (Bortezomib) :

Formula (IIC)

or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of any one of ..claims 1 to 2 and 4 to 7 , wherein the first compound is of Formula (IC) and the second compound is of Formula (IIC) :

Formula (IIC) , or their pharmaceutically acceptable salts thereof .

9. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is^" suitable for oral administration; parenteral administration, intravenous administration; or for topical administration.

10. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is in form of a capsule or tablet or in form of an injectable solution or in form of an aerosol .

11. The pharmaceutical composition of any one of the preceding claims, wherein the salt of the first compound, or tautomer thereof, is an acetate salt.

12. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition further comprises at least one of the following substances: (RS) -2- (2 , 6-dioxopiperidin-3- yl) -lH-isoindole-1, 3 (2H) -dione (Thalidomide),- (RS) - 3- (4-amino-l-oxo-3H-isoindol-2-yl) piperidine-2 , 6- dione (Lenalidomide) , or (RS) -Ν,Ν-bis (2- chloroethyl) -1, 3 , 2-oxazaphosphinan-2-amine 2 -oxide (Cyclophosphamide) .

The pharmaceutical composition of any one of preceding claims, further comprising pharmaceutically acceptable carrier.

A method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of a first compound of Formula (IA) or a pharmaceutically acceptable salt or tautomer.thereof :

Formula ( IA)

Ri , ¾ ¾! R^' 5 f R77 R9 and Rioeach are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, sulfinyl, sulfonyl, carbonyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato ; thiocarbonyl ; thiocyanato,- O-carbamyl; N-carbamyl; O-thiocarbamyl ; or N-thiocarbamyl, and a pharmaceutically effective amount of a second compound of Formula (IIA) or a pharmaceutically acceptable salt thereof:

Formula (IIA)

wherein Rix , R_i2 , 13, ₁₄, and R₁₅ each are independently H; halogen; H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, sulfinyl, sulfonyl, carbonyl, aryl , heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; isocyanato; isothiocyanato; thiocarbonyl ; thiocyanato ; O-carbamyl ; N-carbamyl ,- O-thiocarbamyl ; or N-thiocarbamyl . 15. A method of claim 14, wherein the first compound is of Formula (TA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein R_x, R₂, R₃, R₄ and R₅ each are independently H or CI and the phenyl group is at least substituted twice, and

R₆, R₇, R8_/ R9 and R₁₀ are H, and the second compound is of .. Formula (IIA) , or a pharmaceutically acceptable salt thereof :

Formula (IIA)

wherein R_u , R₁₂ , Ri3 Ri4, and Ri₅ each are independently H; halogen; substituted straight chained, branched or cyclic alkyl; alkoxyl; alkenyl; alkynyl; aryl; CO-alkyl; CO-alkenyl; CO-alkynyl; CO- aryl or heteroaryl; CO-alkoxyalkyl ; CO-aryloxyalkyl ; CO- substituted aryl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; or aralkylsulfonyl .

16. The method of any one of claims 14 or 15, wherein the first compound is of Formula (IB) :

Formula (IB)

or a pharmaceutically acceptable salt or tautomer thereof .

17. The method of any one of claims 14 or 15, wherein the first compound, or tautomer thereof, is of Formula (IC) :

Formula (IC)

or a pharmaceutically acceptable salt or tautomer thereof .

18. The method of any one of claims 14 to 15 and 17, wherein the first compound is 2-(2,6- dichlorobenzylidene) hydrazinecarboximidamide

(Guanabenz) or a pharmaceutical acceptable salt thereof .

19. The method of any one of claims 1 to 18, wherein the pharmaceutically acceptable salt of the first' compound is an acetate salt.

20. The method of any one of claims 14 to 19, wherein the second compound is of Formula (IIB-) , or a pharmaceutically acceptable salt thereof :

21 The method of any one of claims 14 to 20, wherein the second compound is [ (1R) -3 -methyl-1- ( { (2S) -3- phenyl-2- [ (pyrazin-2- ylcarbonyl) amino] propanoyl } amino) butyl] boronic acid (Bortezomib) :

Formula (IIC)

or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of any one of claims 14 to 15 and 17 to 21, wherein the first compound is of Formula (IC) and the second compound is of Formula (IIC) :

or their pharmaceutically acceptable salts thereof.

The method of any one of claims 14 to 22, wherein administration is via oral administration; parenteral administration, intravenous administration; or topical administration.

24. The method of any one of claims 14 to 23, wherein

5. the method further comprises administration of at least one of the following substances: (RS)-2-(2,6- dioxopiperidin-3-yl) -lH-isoindole-1, 3 (2H) -dione (Thalidomide) ,. (RS) -3- (4-amino-l-oxo-3H-isoindol-2- yl) piperidine-2 , 6-dione (Lenalidomide) , or (RS)-N,N-0 bis (2-chloroethyl) -1, 3 , 2 -oxazaphosphinan-2 -amine 2- oxide (Cyclophosphamide) .

25 The method of any one of claims 14 to 24, wherein the first compound and the second compound are administered together or separately.

26 The method of any one of claims 14 to 25, wherein the first compound and the second compound are administered at least once, or at least twice, or at least three times a day.

27 Use of a first compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer5 thereof :

Formula (IA)

wherein R_1; R₂, R₃, R4 R5/ 16 R7 Rs R9 and Ri₀ each are independently H; halogen; optionally substituted alkyl, alkenyl , alkynyl, alkoxy, amino, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl; carboxylic acid; . cyano; nitro; silyl; trimethylsilyl; silylether; methacryloxy; acryloxy; acyloxy; isocyanato; isothiocyanato; sulfinyl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; aralkylsulfonyl ; sulfonamide; thiocarbonyl; thiocyanato; trihalomethanesulfonamido; O-carbamyl; N-carbamyl; 0-thiocarbamyl ; or N-thiocarbamyl , and a second compound of Formula (IIA) , or a pharmaceutically acceptable salt thereof:

Formula (IIA)

wherein Rn, R_i2, R13, R1 , and R_X5 each are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, aryl , heteroaryl, carbocyclyl, or heterocyclyl; hydroxyl; carbonyl; carboxylic acid; cyano; nitro; silyl; trimethylsilyl; silylether; methacryloxy; acryloxy; acyloxy; isocyanato; isothiocyanato; sulfinyl; sulfonyl; alkylsulfonyl ; , arylsulfonyl ; aralkylsulfonyl ; sulfonamide; thiocarbonyl; thiocyanato; trihalomethanesulfonamido; O-carbamyl; N-carbamyl; 0-thiocarbamyl ; or N-thiocarbamyl, in the manufacture of a medicament for treating cancer.

28. The use of claim 27, wherein the first compound is of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof:

Formula ( IA)

wherein Ri , R₂ , R3, R₄ and R₅ each are independently H or Cl and the phenyl group is at least substituted twice, and

R₆ , R₇ , R₈ , R₉ and R₁₀ are H, and the second compound is of Formula (IIA) , or a harmaceutically acceptable salt · thereof :

Formula (IIA)

wherein R_{ll r} R_i2 , R13_/ R14, and R₁₅ each are independently H; optionally halogenated, substituted straight chained, branched or cyclic alkyl; alkoxyl; alkenyl; alkynyl; aryl; CO-alkyl; CO-alkenyl; CO- alkynyl; CO-aryl or heteroaryl; CO-alkoxyalkyl ; CO- aryloxyalkyl ; CO- substituted aryl; sulfonyl; alkylsulfonyl ; arylsulfonyl ; or aralkylsulfonyl , in the manufacture of a medicament for treating cancer.

29. The method or use of any one of claims 14 to 28, wherein the cancer is a clonal plasma cell malignancy.

30. The method or use of any one of claims 14 to 29, wherein the cancer or clonal plasma cell malignancy is multiple myeloma.

31. The method or use of claim 30, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

32. The method or use of claims 30 or 31, wherein the multiple myeloma is Bortezomib-resistant multiple myeloma.

33. A method of treating cancer comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein Ri, R₂ , 3, R4, R5, Re , R7, Rs , R9 and R₁₀ each are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl , alkoxy, amino, aryl, heteroaryl, carbocyclyl, or heterocyclyl ; hydroxyl ; carboxylic acid; cyano; nitro; silyl; trimethylsilyl ; silylether; methacryloxy; acryloxy; acyloxy; isocyanato; isothiocyanato; sulfinyl; sulfonyl; alkylsulfonyl ; arylsulfonyl aralkylsulfonyl ; sulfonamide; thiocarbonyl thiocyanato; trihalomethanesulfonamido; O-carbamyl N-carbamyl; O-thiocarbamyl ; or N-thiocarbamyl.

34. The method of claim 33, wherein the compound is of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula ( IA)

wherein R₁₍ R₂, R3, R₄ and R₅ each are independently H or CI and the phenyl group is at least substituted twice, and

R₆, R₇, R₈, R9 and R₁₀ are H.

35 The method of any one of claims 33 or 34, wherein the compound is of Formula (IB) :

Formula (IB)

or a pharmaceutically acceptable salt or tautomer thereof .

The method of any one of claims 33 or 34, whe the compound is of Formula (IC) :

Formula (IC)

or a pharmaceutically acceptable salt or tautomer til-#areof;..

37. The method of any one of claims 33 or 34 and 36, wherein the compound is 2- (2, 6- dichlorobenzylidene) hydrazinecarboximidamide

(Guanabenz) or a pharmaceutically acceptable salt thereof .

38. The method of any one of claims 33 to 37, wherein the pharmaceutically acceptable salt is an acetate salt . .

39. The method of any one of claims 33 to 38, wherein administration is via oral administration; parenteral administration; intravenous administration; or topical administration.

40. The method of any one of claims 33 to 39, wherein the method further comprises administration of at least one of the following substances: (RS)-2-(2,6- dioxopiperidin-3-yl) -lH-isoindole-1, 3 (2H) -dione

(Thalidomide) , (RS) -3- (4-amino-l-oxo-3H-isoindol-2- yl) piperidine-2 , 6-dione (Lenalidomide) , or (RS) -N, - bis (2-chloroethyl) -1,3, 2-oxazaphosphinan-2-amine 2- oxide (Cyclophosphamide) . Use of a compound of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof :

Formula (IA)

wherein R₁₍ R₂, R3, R₄, R₅, R6_/ R₇, Rs, R₉ and ^'R₁₀ each are independently H; halogen; optionally substituted alkyl, alkenyl, alkynyl, alkoxy, amino, aryl, heteroaryl, carbocyclyl, or heterocyclyl; hydroxy1 carboxylic acid; cyano; nitro; silyl trimethylsilyl ; silylether; methacryloxy; acryloxy acyloxy; isocyanato; isothiocyanato; sulfinyl sulfonyl; alkylsulfonyl ; arylsulfonyl aralkylsulfonyl ; sulfonamide; thiocarbonyl thiocyanato; trihalomethanesulfonamido ; O-carbamyl N-carbamyl; O-thiocarbamyl ; or N-thiocarbamyl, in the manufacture of a medicament for treating cancer. 42. The use of claim 41, wherein the compound is of Formula (IA) , or a pharmaceutically acceptable salt or tautomer thereof : w Independently H

or CI and the phenyl, group is at least substituted twice, and

R₆ , R₇ , R₈ , R₉ and Ri₀ are H.

43. The method or use of any one of claims 33 to 42,

. wherein the cancer is a clonal plasma cell malignancy.

44. The method or use of any one of claims 33 to 43, wherein the cancer or clonal plasma cell malignancy is multiple myeloma.

The method or use of claim 44, wherein the multiple myeloma is relapsed or refractory multiple myeloma.

The method or use of claims 44 or 45, wherein the multiple myeloma is Bortezomib- resistant multiple myeloma.