WO2016187667A1 - Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux - Google Patents
Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux Download PDFInfo
- Publication number
- WO2016187667A1 WO2016187667A1 PCT/AU2016/050407 AU2016050407W WO2016187667A1 WO 2016187667 A1 WO2016187667 A1 WO 2016187667A1 AU 2016050407 W AU2016050407 W AU 2016050407W WO 2016187667 A1 WO2016187667 A1 WO 2016187667A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- dimethyl
- methyl
- indol
- methylpiperazin
- Prior art date
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- UQCZTYYOUWMXCF-UHFFFAOYSA-N methyl 3-[(2,3-dimethyl-1H-indol-5-yl)methyl]benzoate Chemical compound CC=1NC2=CC=C(C=C2C=1C)CC=1C=C(C(=O)OC)C=CC=1 UQCZTYYOUWMXCF-UHFFFAOYSA-N 0.000 description 3
- WQQSTNYWRUVXPZ-UHFFFAOYSA-N methyl 3-[(2,3-dimethyl-1H-indol-5-yl)oxy]benzoate Chemical compound CC=1NC2=CC=C(C=C2C=1C)OC=1C=C(C(=O)OC)C=CC=1 WQQSTNYWRUVXPZ-UHFFFAOYSA-N 0.000 description 3
- YZOCVDYIFHFWDW-UHFFFAOYSA-N methyl 3-[1-(3-chloropropyl)-2,3-dimethylindol-5-yl]oxybenzoate Chemical compound ClCCCN1C(=C(C2=CC(=CC=C12)OC=1C=C(C(=O)OC)C=CC=1)C)C YZOCVDYIFHFWDW-UHFFFAOYSA-N 0.000 description 3
- UXIAXNRMHRTYMN-UHFFFAOYSA-N methyl 3-[2,3-dimethyl-1-[3-(4-methylpiperazin-1-yl)propyl]indol-5-yl]oxybenzoate Chemical compound CC=1N(C2=CC=C(C=C2C=1C)OC=1C=C(C(=O)OC)C=CC=1)CCCN1CCN(CC1)C UXIAXNRMHRTYMN-UHFFFAOYSA-N 0.000 description 3
- FILFNBKSVOHNPK-UHFFFAOYSA-N methyl 3-[[1-(3-chloropropyl)-2,3-dimethylindol-5-yl]methyl]benzoate Chemical compound ClCCCN1C(=C(C2=CC(=CC=C12)CC=1C=C(C(=O)OC)C=CC=1)C)C FILFNBKSVOHNPK-UHFFFAOYSA-N 0.000 description 3
- DXQGVNGGQMAPTQ-UHFFFAOYSA-N methyl 3-[[2,3-dimethyl-1-[2-methyl-3-(4-methylpiperazin-1-yl)propyl]indol-5-yl]methyl]benzoate Chemical compound CC=1N(C2=CC=C(C=C2C=1C)CC=1C=C(C(=O)OC)C=CC=1)CC(CN1CCN(CC1)C)C DXQGVNGGQMAPTQ-UHFFFAOYSA-N 0.000 description 3
- HYFJDBWPIAFVSM-UHFFFAOYSA-N methyl 3-[[2,3-dimethyl-1-[3-(4-methylpiperazin-1-yl)propyl]indol-5-yl]methyl]benzoate Chemical compound CC=1N(C2=CC=C(C=C2C=1C)CC=1C=C(C(=O)OC)C=CC=1)CCCN1CCN(CC1)C HYFJDBWPIAFVSM-UHFFFAOYSA-N 0.000 description 3
- BXJFWGNKTYBPEA-UHFFFAOYSA-N methyl 4-[(2,3-dimethyl-1H-indol-5-yl)oxy]benzoate Chemical compound CC=1NC2=CC=C(C=C2C=1C)OC1=CC=C(C(=O)OC)C=C1 BXJFWGNKTYBPEA-UHFFFAOYSA-N 0.000 description 3
- KIWRZJZGNLXTIL-UHFFFAOYSA-N methyl 4-[1-(3-chloropropyl)-2,3-dimethylindol-5-yl]oxybenzoate Chemical compound ClCCCN1C(=C(C2=CC(=CC=C12)OC1=CC=C(C(=O)OC)C=C1)C)C KIWRZJZGNLXTIL-UHFFFAOYSA-N 0.000 description 3
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates broadly to functionalised and substituted indoles, the preparation thereof and their use in the treatment of proliferative diseases such as cancer.
- patients with breast cancer have benefited from early screening programs as well as a variety of surgical techniques. However, these often prove physically and emotionally debilitating.
- patients who have undergone surgery and subsequent chemotherapy often experience a recurrence in their disease.
- a potential new method of specifically attacking cancer cells is through disruption of cancer cells' cellular skeletal system which is comprised predominantly of actin.
- the actin cytoskeleton is intimately involved in cell division and cell migration.
- actin plays a ubiquitous role as the cytoskeleton of tumor cells and the actin filaments of the muscle sarcomere.
- the differing roles but similarity in structure make actin a difficult target for drug development due to unwanted off- target side effects.
- the invention seeks to address one or more of the above mentioned problems, and/or to provide improvements in cancer therapy.
- the present invention provides a compound of the formula (I),
- R 1 and R 2" are independently selected from the group consisting of hydrogen and Ci- C 6 alkyl
- R 3 J is NR 8°R 1 1 0 U or a 4- to 7-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N, O, S, or NR 6 and wherein the ring is optionally substituted with R ;
- R 4 is a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N, O, S, or NR 6 ;
- each Y is independently OH or Ci-C 6 alkoxy and X is a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N or NR 6 and wherein the ring is optionally substituted with between 1 and 3 substituents selected from the group consisting of: halo and Ci-C 6 alkyl, or
- R 5 is wherein Z is OH or Ci-C 6 alkoxy and Q is selected from the group consisting of: halo, -S0 2 Ci-C 6 alkyl, -(CH 2 )o- 5 COOH, -(CH ⁇ o-sCOOQ-Ce alkyl or a 5- or 6-membered carbocyclic ring wherein between 1 and 4 carbons may optionally be replaced by N or NR 6 ;
- R 6 is selected from the group consisting of: H and Ci-C 6 alkyl; R is selected from the group consisting of: H, halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, CN, CF 3 and OCF 3 ;
- R 8° and R 1 1 0 U are independently selected from the group consisting of: H and Ci-C 6 alkyl;
- X 1 is an alkanediyl group having between 1 and 20 carbon atoms
- X 3 are independently selected from the group consisting of: -0-, -NH-, -NCi- C 6 alkyl-, -C(O)-, -C(0)NH-, -NHC(O)- or an alkanediyl group having between 1 and 20 carbon atoms wherein between 1 and 3 hydrogen atoms may optionally be replaced with R .
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) according to the first aspect together with a pharmaceutically acceptable carrier, diluent or excipient.
- the present invention provides a method for the treatment of a proliferative disease in a subject in need thereof, the method comprising administration to the subject of a therapeutically effective amount of a compound of formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect.
- the present invention provides use of a compound of formula (I) according to the first aspect in the manufacture of a medicament for the treatment of a proliferative disease.
- the present invention provides use of a compound of formula (I) according to the first aspect or a pharmaceutical composition according to the second aspect for the treatment of a proliferative disease in a subject.
- the present invention provides a compound of formula (I) according to the first aspect or a pharmaceutical composition according to the second aspect for use in the treatment of a proliferative disease in a subject.
- the proliferative disease may be cancer, such as for example a solid tumour.
- the cancer is selected from the group consisting of: breast cancer, lung cancer, prostate cancer, ovarian cancer, uterine cancer, brain cancer, skin cancer, colon cancer, bladder cancer, melanoma and neuroblastoma.
- the cancer may be a cancer that has recurred.
- the present invention provides a method for reducing incidences of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence, the method comprising administration to the subject of an effective amount of a compound of formula (I) according to the first aspect, or a pharmaceutical composition according to the second aspect.
- the present invention provides use of a compound of formula (I) according to the first aspect in the manufacture of a medicament for reducing incidences of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.
- the present invention provides a compound of formula (I) according to the first aspect for use in reducing incidences of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.
- the present invention provides use of a compound of formula (I) according to the first aspect for reducing incidences of, or risk of, cancer recurrence in a subject deemed to be at risk of cancer recurrence.
- the subject may be a subject who is in cancer remission.
- the present invention provides a combination comprising:
- the combination may be a synergistic combination.
- the present invention provides a pharmaceutical composition comprising:
- composition (iii) a pharmaceutically acceptable carrier, diluent or excipient.
- the composition may be a synergistic composition.
- the present invention provides a kit comprising:
- compositions are intended for simultaneous, concurrent, separate or sequential use.
- the present invention provides a method for the treatment of cancer in a subject in need thereof, the method comprising administration to the subject of a therapeutically effective amount of a compound of formula (I) according to the first aspect, and a therapeutically effective amount of vincristine or paclitaxel.
- the cancer may be melanoma, lung cancer or prostate cancer.
- Administration of the compound of formula (I) and vincristine or paclitaxel may be simultaneous, concurrent, separate or sequential.
- the compound of formula (I) may be selected from one or more of compounds 6, 8, 14, 16, 23, 24, 27, 31, 32, 38, 39, 47, 48, 51, 55, 58, 60, 63, 67 and 68.
- an element means one element or more than one element.
- alkyl is taken to mean straight chain or branched chain monovalent saturated hydrocarbon groups having the recited number of carbon atoms.
- alkyl groups include, but are 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, 4-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,
- alkoxy is taken to mean O-alkyl groups in which alkyl is as defined herein.
- alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, sec-butoxy and tert-butoxy.
- halogen and halo are synonymous and refer to fluorine, chlorine, bromine or iodine.
- alkanediyl is understood to refer to a bivalent saturated branched or straight chain hydrocarbon group conforming to the formula C n H 2n .
- carrier ring refers to a ring structure in which all of the ring members are carbon atoms.
- pharmaceutically acceptable salt refers to those salts which, within the scope of sound medical judgement, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- prodrug means a compound which is able to be converted in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the formula (I).
- metabolic means e.g. by hydrolysis, reduction or oxidation
- an ester prodrug of a compound of the present invention containing a hydroxy group may be hydrolysed in vivo to the parent molecule.
- Suitable esters are for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ - hydroxynaphthoates, gestisates, isethionates, di-/?-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, /?-toluenesulfonates, cyclohexylsulfamates and quinates.
- treating refers to any and all uses which remedy a proliferative disease or symptoms thereof, prevent the establishment of a proliferative disease, or otherwise prevent, hinder, retard or reverse the progression of a proliferative disease or other undesirable symptoms in any way whatsoever.
- treating does not necessarily imply that a subject is treated until total recovery.
- terapéuticaally effective amount includes a non-toxic but sufficient amount of an active compound to provide the desired therapeutic effect. Those skilled in the art will appreciate that the exact amount of a compound required will vary based on a number of factors and thus it is not possible to specify an exact “therapeutically effective amount”. However, for any given case an appropriate “therapeutically effective amount” may be determined by one of ordinary skill in the art.
- an effective amount includes a non-toxic but sufficient amount of an active compound to provide the stated effect.
- effective amount means an amount of a compound of formula (I) that is required to reduce the incidence of, or risk of an individual experiencing cancer recurrence.
- Those skilled in the art will appreciate that the exact amount of a compound required will vary based on a number of factors and 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.
- a “pharmaceutical carrier, diluent or excipient” includes, but is not limited to, any physiological buffered (i.e., about pH 7.0 to 7.4) medium comprising a suitable water-soluble organic carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.
- suitable water-soluble organic carriers include, but are not limited to saline, dextrose, corn oil, dimethylsulfoxide, and gelatin capsules.
- lactose lactose
- mannitol corn starch
- potato starch binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins, disintegrators, such as sodium carboxymethyl-cellulose, and lubricants such as talc or magnesium stearate.
- binders such as crystalline cellulose, cellulose derivatives, acacia, gelatins
- disintegrators such as sodium carboxymethyl-cellulose
- lubricants such as talc or magnesium stearate.
- subject includes any human or non-human animal.
- the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs.
- the term "recurrence" as it relates to cancer is understood to mean the return of cancerous cells and/or a cancerous tumour after cancerous cells and/or a cancerous tumour have been successfully treated previously.
- the term “administering” and variations of that term including “administer” and “administration”, include contacting, applying, delivering or providing a compound or composition of the invention to an organism, or a surface by any appropriate means.
- Figure 1 Imaging and quantitation of actin filaments in SK-N-SH neuroblastoma cells treated with compound (A) 50, (B) 51.
- Cells were stained with 488-Atto-Phallodin and DAPI to visualize the actin filament bundles and the nucleus, respectively.
- Shown in the top panel is a representative gray scale immunofluorescent image from control (vehicle alone), 2.5 ⁇ and 5 ⁇ treated cells, overlayed with the linear feature quantitation. The coloured lines indicate the detected actin filaments.
- Also shown is the quantitation of cell number and filament number/cell.
- Statistical analysis was performed using a one way ANNOVA-multiple comparison where each drug-treated group was compared to the control. **** p ⁇ 0.0001, **** p ⁇ 0.001, *** p ⁇ 0.01, ** p ⁇ 0.1.
- FIG. 2 Imaging and quantitation of actin filaments in SK-N-SH neuroblastoma cells treated with compound (A) 50 and (B) 51.
- Cells were stained with j9d primary antibody (MAb culture s/n clone 2G10.2, 1 :50) followed by 488- conjugated secondary antibody (Goat anti mouse 488, 1: 1000) and DAPI to visualize the Tpm3.1 containing filament bundles and the nucleus, respectively.
- Shown in the top panel (enlarged inset bottom panel) is a representative gray scale immunofluorescent image from control (vehicle alone), 2.5 ⁇ and 5 ⁇ treated cells, overlayed with the linear feature quantitation. The coloured lines indicate the detected actin filaments.
- FIG. 3 Plate layout for drug combination assays. Each screening plate contained up to six 6x6 dose matrix along with assay controls (thonzonium bromide and DMSO) as indicated. The rest of the wells contained cells only. Individual drug doses within the matrix were based on the established IC 50 concentrations for the two drugs using two-fold dilution steps. Each drug combination was tested in triplicate.
- the present invention is based on the surprising finding by the inventors that compounds of the general formula (I) effectively inhibit tropomyosin which results in an unexpected improvement in the treatment of proliferative diseases, particularly cancer.
- actin cytoskeleton involves a number of ancillary control and regulatory proteins. Identification and specific targeting of actin regulatory proteins associated with the cytoskeleton of cancer cells provides the opportunity to develop cancer- specific drugs lacking unwanted side effects.
- Actin filaments are constructed through the polymerisation of globular actin protein monomers.
- the actin monomer is polar, with one end bearing a positive charge and the other end a negative charge.
- the actin filaments thus have all the actin proteins aligned in one direction.
- These filaments have secondary coiled proteins, tropomyosins, associated with them.
- the tropomyosins play an integral role in regulating the function of actin filaments.
- the actin filaments are made up of polymeric actin monomers with tropomyosin dimers sitting in the alpha helical groove of the actin filament to form a homopolymer.
- tropomyosin isoforms there are more than 40 mammalian tropomyosin isoforms, each of which regulates specific actin filaments.
- tropomyosins that regulate the cytoskeleton of cancer cells; disruption of this interaction offers a basis to treat cancer cells with a high degree of specificity.
- the present invention provides a compound of the formula (I),
- R 1 and R 2" are independently selected from the group consisting of hydrogen and Ci- C 6 alkyl
- R 3 J is NR 8°R 1 1 0 U or a 4- to 7-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N, O, S, or NR 6 and wherein the ring is optionally substituted with R ;
- R 4 is a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N, O, S, or NR 6 ;
- each Y is independently OH or Ci-C 6 alkoxy and X is a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N or NR 6 and wherein the ring is optionally substituted with between 1 and 3 substituents selected from the group consisting of: halo and Ci-C 6 alkyl, or
- R is Q wherein Z is OH or Ci-C 6 alkoxy and Q is selected from the group consisting of: halo, -S0 2 Ci-C 6 alkyl, -(CH 2 )o- 5 COOH, -(CH ⁇ o-sCOOQ-Ce alkyl or a 5- or 6-membered carbocyclic ring wherein between 1 and 4 carbons may optionally be replaced by N or NR 6 ;
- R 6 is selected from the group consisting of: H and Ci-C 6 alkyl; R is selected from the group consisting of: H, halo, Ci-C 6 alkyl, Ci-C 6 alkoxy, CN, CF 3 and OCF 3 ;
- R 8° and R 1 1 0 U are independently selected from the group consisting of: H and Ci-C 6 alkyl;
- X 1 is an alkanediyl group having between 1 and 20 carbon atoms
- X 2" and X 3 3 are independently selected from the group consisting of: -0-, -NH-, -NCi- C 6 alkyl-, -C(O)-, -C(0)NH-, -NHC(O)- or an alkanediyl group having between 1 and 20 carbon atoms wherein between 1 and 3 hydrogen atoms may optionally be replaced with R .
- R 1 and R 2 are independently selected from the group consisting of: H and Ci-C 3 alkyl.
- R 1 and R 2 are independently selected from the group consisting of: H and methyl.
- R 1 and R 2 are both methyl.
- R 3 is NR 8 R 10 or a 4- to 7-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N or NR 6 and wherein the ring is optionally substituted with R .
- R 3 is NR 8 R 10 or a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N or NR 6 and wherein the ring is optionally substituted with Ci-C 6 alkyl.
- R 3 is NR 8 R 10 or a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N or NR 6 .
- R is N(Me) 2 , NH 2 or a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N or NR 6 .
- R is N(Me) 2 , NH 2 or a 5- or 6-membered carbocyclic ring wherein 1 or 2 carbons may optionally be replaced by N or NR 6 .
- R is N(Me) 2 , NH 2 or a 6-membered carbocyclic ring wherein 1 or 2 carbons may optionally be replaced by N, NH or NMe.
- R is N(Me) 2 or a 6-membered carbocyclic ring wherein 1 or 2 carbons may optionally be replaced by N, NH or NMe.
- R is N(Me) 2 , NH 2 or a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N, S, O or NR 6 .
- the 4- to 7-membered carbocyclic ring and the 5- or 6- membered carbocyclic ring may be saturated or partially saturated.
- R is selected from the group consisting of: N(Me) 2 ,
- R is selected from the group consisting of: N(Me) 2
- odiment R is selected from the group consisting of:
- R 4 is a 5- or 6-membered carbocyclic ring wherein between 1 and 3 carbons may optionally be replaced by N, NR 6 , O or S.
- R 4 is phenylene or a 5- or 6-membered heteroarylene ring having between 1 and 3 heteroatoms selected from the group consisting of: N, O and S.
- R 4 is phenylene or a 5- or 6-membered heteroarylene ring having between 1 and 3 N heteroatoms.
- R 4 is phenylene or a 6-membered heteroarylene ring having between 1 and 3 N heteroatoms.
- R 4 is phenylene or pyridylene.
- R 4 is phenylene
- R 4 is para-phenylene or meta-phenylene.
- R 5 is wherein Y is OH or OMe and X is phenyl or a 5- or 6-membered heteroaryl ring having between 1 and 3 heteroatoms selected from the group consisting of: N, O and S,and wherein the phenyl and the heteroaryl ring may optionally be substituted with 1 or 2 substituents selected from the group consisting of: halo, methyl, ethyl, propyl and isopropyl, or
- R is Q wherein Z is OH or OMe and Q is selected from the group consisting of: halo, -S0 2 Me, -(CH 2 ) 0 - 5 COOH, -(CH 2 ) 0 - 5 COOCi-C 6 alkyl, phenyl and a 5- or 6-membered heteroaryl ring having between 1 and 4 N heteroatoms.
- R 5 is Y is OH or OMe and X is or a 5- or 6- membered heteroaryl ring having between 1 and 3 N heteroatoms, and wherein the phenyl and the heteroaryl ring may optionally be substituted with 1 or 2 halo substituents, or
- R 5 is wherein Z is OH or OMe and Q is selected from the group consisting of: halo, -S0 2 Me, -(CH 2 )i- 5 COOH, phenyl and a 5- or 6-membered heteroaryl ring having between 1 and 4 N heteroatoms.
- R 5 is Y is OH or OMe and X is phenyl or a 5- or 6-membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl and the heteroaryl ring may optionally be substituted with a halo substituent, or
- R 5 is wherein Z is OH or OMe and Q is selected from the group consisting of: I, -S0 2 Me, -(CH 2 )i_ 3 COOH, or a 5-membered heteroaryl ring having between 1 and 4 N heteroatoms.
- R 5 is wherein Y is OH or OMe and X is phenyl or a 5- or 6-membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl and the heteroaryl ring may optionally be substituted with a fluoro substituent, or
- R is Q wherein Z is OH and Q is selected from the group consisting of: I, -S0 2 Me, -(CH 2 ) 2 COOH, or a 5-membered heteroaryl ring having between 1 and 4 N heteroatoms.
- R is Y is OH or OMe and
- X is phenyl or a 5- or 6-membered heteroaryl ring having 1 or 2 N heteroatoms, and wherein the phenyl and the heteroaryl ring may optionally be substituted with a fluoro substituent, or
- R is Q wherein Z is OH and Q is selected from the group consisting of: I, -S0 2 Me, -(CH 2 ) 2 COOH and tetrazolyl.
- R 5 is
- R 5 is
- R 6 is selected from the group consisting of H, methyl and ethyl.
- R 6 is selected from the group consisting of H and methyl.
- X 1 is an alkanediyl group having between 1 and 15 carbon atoms.
- X 1 is an alkanediyl group having between 1 and 10 carbon atoms.
- X 1 is an alkanediyl group having between 1 and 6 carbon atoms.
- X 1 is - (CH 2 ) 1-6 - or -CH 2 -CH(Me)-(CH 2 )-. In yet another embodiment X 1 is - (CH 2 ) 2 _ 5 - or -CH 2 -CH(Me)-(CH 2 )-.
- X 2 and X 3 are independently selected from the group consisting of: -0-, -NH-, -NCi-C 6 alkyl-, -C(O)-, -C(0)NH-, -NHC(O)- and an alkanediyl group having between 1 and 15 carbon atoms.
- X 2 and X 3 are independently selected from the group consisting of: -0-, -NH-, -NMe, -C(0)NH-, -NHC(O)- and an alkanediyl group having between 1 and 10 carbon atoms.
- X 2 and X 3 are independently selected from the group consisting of: -0-, -NH-, -NMe, -C(0)NH-, -NHC(O)- and an alkanediyl group having between 1 and 6 carbon atoms.
- X 2 and X 3 are independently selected from the group consisting of: -0-, -NH-, -C(0)NH-, -NHC(O)-, -CH 2 CH 2 CH 2 -, CH 2 CH 2 - and - CH 2 -.
- X 2 and X 3 are independently selected from the group consisting of: -0-, -NH-, -C(0)NH-, -NHC(O)- and CH 2 .
- X is selected from the group consisting of: -0-, -NH- and -CH 2 -.
- X 3 is -C(0)NH- or -NHC(O)-.
- exemplary compounds of the formula (I) include the following:
- the compounds are:
- the compound of formula (I) is selected from the group consisting of: compounds 9-12, 17-20, 22-24, 30-32, 44, 46-52 and 69-72.
- the compound of formula (I) is selected from the group consisting of: compounds 1-12, 14-20, 26-28, 33-36, 38-40, 42-44 and 46-72.
- the compound of formula (I) is selected from the group consisting of: compounds 22-24 and 30-32. In yet another embodiment the compound of formula (I) is selected from the group consisting of: compounds 6, 8, 16, 23, 24, 47, 48, 51, 60 and 68.
- the compounds of formula (I) may include one or more chiral centres.
- the present invention includes all enantiomers and diastereoisomers as well as mixtures thereof in any proportions.
- the invention also extends to isolated enantiomers or pairs of enantiomers. Methods of separating enantiomers and diastereoisomers are well known to persons skilled in the art.
- compounds of the formula (I) are racemic mixtures.
- compounds of the formula (I) are present in optically pure form.
- Solvates are complexes formed by association of molecules of a solvent with a compound of the formula (I).
- compounds of the formula (I) that are solids, it will be understood by those skilled in the art that such compounds may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention.
- the compounds of formula (I) may be in the form of pharmaceutically acceptable salts. Such salts are well known to those skilled in the art. S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of compounds of the formula (I), or separately by reacting the free base compound with a suitable organic acid. Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
- Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, fumaric, maleic, pyruvic, alkyl sulfonic, arylsulfonic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, ambonic, pamoic, pantothenic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, ⁇ -hydroxybutyric, galactaric, and galacturonic acids.
- Suitable pharmaceutically acceptable base addition salts of the compounds of the present invention include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
- the compounds of formula (I) also extend to include all derivatives with physiologically cleavable leaving groups that can be cleaved in vivo to provide the compounds of the formula (I).
- Suitable leaving groups include acyl, phosphate, sulfate, sulfonate, and preferably are mono-, di- and per-acyl oxy-substituted compounds, where one or more of the pendant hydroxy groups are protected by an acyl group, preferably an acetyl group.
- acyloxy substituted compounds are readily cleavable to the corresponding hydroxy-substituted compounds.
- compound (III) could be hydrolysed to give the free acid and subsequently reacted with R 5 NH 2 prior to functionalisation of the 1 -position of the indole to introduce the X 1 R 3 substituent.
- This alternative synthetic route is shown in Scheme 2 below.
- Compounds of the formula (I) may be used in the treatment or prevention of proliferative diseases such as cancer.
- the compounds and pharmaceutical compositions of the invention may be useful for the treatment of a wide variety of cancers, including but not limited to, solid tumours such as breast cancer, lung cancer (NSCLC and SCLC), prostate cancer, ovarian cancer, uterine cancer, peritoneal cancer, brain cancer (including, for example, gliomas such as glioblastoma, Diffuse Intrinsic Pontine Glioma (DIPG) and medulloblastoma), skin cancer, colon cancer, bladder cancer, colorectal cancer, gastric cancer, liver cancer, pancreatic cancer, head and neck cancer, melanoma, malignant ascites, mesothelioma and neuroblastoma.
- the cancer is selected from the group consisting of: prostate cancer, lung cancer, breast cancer, colorectal cancer, melanoma and neuroblastoma.
- the cancer may be
- Compounds of the formula (I) may also find use in treating cancer that has recurred and in reducing the incidence of, or the risk of, recurrence of cancer in a subject deemed to be at risk of cancer recurrence, for example a subject who is in cancer remission.
- the subject may be in remission from a solid tumour as defined herein.
- compounds of the formula (I) may possess superior pharmaceutical properties, such as improved resistance to conjugation via glucuronyl transferases and other water-solubilising transferases such as sulfases, which may be over-expressed on proliferative cells, such as cancer cells.
- superior pharmaceutical properties such as an enhanced pharmacokinetic profile through reduced conjugation and elimination.
- compounds and pharmaceutical compositions of the present invention may be administered via any route which delivers an effective amount of the compounds to the tissue or site to be treated.
- the compounds and compositions may be administered by the parenteral (for example intravenous, intraspinal, subcutaneous or intramuscular), oral or topical route. Administration may be systemic, regional or local. In one embodiment administration may be rectal.
- the particular route of administration to be used in any given circumstance will depend on a number of factors, including the nature of the cancer to be treated, the severity and extent of the cancer, the required dosage of the particular compound to be delivered and the potential side-effects of the compound.
- suitable compositions may be prepared according to methods that are known to those of ordinary skill in the art and may include pharmaceutically acceptable carriers, diluents and/or excipients.
- the carriers, diluents and excipients must be "acceptable” in terms of being compatible with the other ingredients of the composition, and not deleterious to the recipient thereof.
- Examples of pharmaceutically acceptable carriers or diluents are demineralised or distilled water; saline solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil, maize oil or coconut oil; silicone oils, including polysiloxanes, such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysiloxane; volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose or hydroxypropylmethylcellulose; Cremaphor; cyclodextrins; lower alkanols, for example ethanol or i-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene glycols, for example polyethylene glycol, polypropylene glycol, ethylene glycol, propylene glycol, 1,3-butylene glyco
- compositions of the invention may be in a form suitable for administration by injection, in the form of a formulation suitable for oral ingestion (such as capsules, tablets, caplets, elixirs, for example), in the form of an ointment, cream or lotion suitable for topical administration, in a form suitable for delivery as an eye drop, in an aerosol form suitable for administration by inhalation, such as by intranasal inhalation or oral inhalation, in a form suitable for parenteral administration, that is, subcutaneous, intramuscular or intravenous injection.
- a formulation suitable for oral ingestion such as capsules, tablets, caplets, elixirs, for example
- an ointment cream or lotion suitable for topical administration
- an eye drop in an aerosol form suitable for administration by inhalation, such as by intranasal inhalation or oral inhalation
- parenteral administration that is, subcutaneous, intramuscular or intravenous injection.
- non-toxic parenterally acceptable diluents or carriers can include cyclodextrins (for example Captisol®) Cremaphor, Ringer's solution, isotonic saline, phosphate buffered saline, ethanol and 1,2 propylene glycol.
- cyclodextrins for example Captisol®
- the compounds may also be added to PEG and non-PEGylated liposomes or micelles with specific targeting tags attached to PEG moieties, such as the RGD peptide or glutathione, for aiding passage across the blood brain barrier.
- suitable carriers, diluents, excipients and adjuvants for oral use include cyclodextrins, Cremaphor, peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatine and lecithin.
- these oral formulations may contain suitable flavouring and colourings agents.
- the capsules When used in capsule form the capsules may be coated with compounds such as glyceryl monostearate or glyceryl distearate that delay disintegration.
- Adjuvants typically include emollients, emulsifiers, thickening agents, preservatives, bactericides and buffering agents.
- Solid forms for oral administration may contain binders acceptable in human and veterinary pharmaceutical practice, sweeteners, disintegrating agents, diluents, flavourings, coating agents, preservatives, lubricants and/or time delay agents.
- Suitable binders include gum acacia, gelatine, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol.
- Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
- Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar.
- Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate.
- Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
- Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
- Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
- Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc.
- Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
- Liquid forms for oral administration may contain, in addition to the above agents, a liquid carrier.
- suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.
- Suspensions for oral administration may further comprise dispersing agents and/or suspending agents.
- Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or acetyl alcohol.
- Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono- or di-oleate, -stearate or -laurate, polyoxyethylene sorbitan mono- or di-oleate, -stearate or -laurate and the like.
- Emulsions for oral administration may further comprise one or more emulsifying agents.
- Suitable emulsifying agents include dispersing agents as exemplified above or natural gums such as guar gum, gum acacia or gum tragacanth.
- parenterally administrable compositions are apparent to those skilled in the art, and are described in more detail in, for example, Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pa., hereby incorporated by reference herein.
- Topical formulations may comprise an active ingredient together with one or more acceptable carriers, and optionally any other therapeutic ingredients.
- Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site where treatment is required, such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
- Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions. These may be prepared by dissolving the active ingredient in an aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container and sterilised. Sterilisation may be achieved by autoclaving or maintaining at 90 °C to 100 °C for half an hour, or by filtration, followed by transfer to a container by an aseptic technique.
- bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
- Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
- Lotions according to the present invention include those suitable for application to the skin or eye.
- An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those described above in relation to the preparation of drops.
- Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisiteriser such as glycerol, or oil such as olive oil.
- Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with a greasy or non-greasy basis.
- the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol, such as propylene glycol or macrogols.
- composition may incorporate any suitable surfactant such as an anionic, cationic or non-ionic surfactant, such as sorbitan esters or polyoxyethylene derivatives thereof.
- suitable surfactant such as an anionic, cationic or non-ionic surfactant, such as sorbitan esters or polyoxyethylene derivatives thereof.
- Suspending agents such as natural gums, cellulose derivatives or inoraganic materials such as silicaceous silicas, and other ingredients such a lanolin, may also be included.
- compositions are administered in the form of suppositories suitable for rectal administration of the compounds of formula (I).
- suppositories suitable for rectal administration of the compounds of formula (I).
- These compositions are prepared by mixing the compound of formula (I) with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the compound of formula (I).
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the compound of formula (I).
- suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
- compositions may also be administered or delivered to target cells in the form of liposomes.
- Liposomes are generally derived from phospholipids or other lipid substances and are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
- liposomes used in administering or delivering a composition to target cells are synthetic cholesterol (Sigma), the phospholipid l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); Avanti Polar Lipids), the PEG lipid 3-N-[(-methoxy poly(ethylene glycol)2000)carbamoyl]-l,2-dimyrestyloxy-propylamine (PEG-cDMA), and the cationic lipid l,2-di-o-octadecenyl-3-(N,N-dimethyl)aminopropane (DODMA) or 1,2- dilinoleyloxy-3-(N,N-dimethyl)aminopropane (DLinDMA) in the molar ratios 55:20: 10: 15 or 48:20:2:30, respectively, PEG-cDMA, DODMA and DLinDMA.
- DSPC phospholipid l,2-distearoyl
- the liposome may be contracted from l,2-distearoyl-sn-glycero-3-phosphoethanolamine- N-[methoxy(polyethylene glycol)-2000] (DSPE PEG2000) and phosphatidylcholine derived from soy and hydrogenated between 50-100%, for example Soy PC-75 or Soy PC- 100. Differing MW PEG's may be used and covalently bound with various specific targeting agents such as glutathione, RGD peptides or other recognized liposome targeting agents. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used.
- the compositions in liposome form may contain stablisers, preservatives, excipients and the like.
- the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
- Methods to form liposomes are known in the art, and in relation to this, specific reference is made to: Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq., the contents of which is incorporated herein by reference.
- compositions may also be administered in the form of microparticles or nanoparticles.
- Biodegradable microparticles formed from polyactide (PLA), polylactide-co-glycolide (PLGA), and epsilon-caprolactone ( ⁇ -caprlactone) have been extensively used as drug carriers to increase plasma half life and thereby prolong efficacy (R. Kumar, M., 2000, J. Pharm. Pharmaceut. Sci. 3(2) 234-258).
- Microparticles have been formulated for the delivery of a range of drug candidates including vaccines, antibiotics, and DNA. Moreover, these formulations have been developed for various delivery routes including parenteral subcutaneous injection, intravenous injection and inhalation.
- compositions may incorporate a controlled release matrix that is composed of sucrose acetate isobutyrate (SAIB) and an organic solvent or organic solvents mixture.
- SAIB sucrose acetate isobutyrate
- Polymer additives may be added to the vehicle as a release modifier to further increase the viscosity and slow down the release rate.
- SAIB is a well known food additive. It is a very hydrophobic, fully esterified sucrose derivative, at a nominal ratio of six isobutyrate to two acetate groups. As a mixed ester, SAIB does not crystallise but exists as a clear viscous liquid. Mixing SAIB with a pharmaceutically acceptable organic solvent, such as ethanol or benzyl alcohol decreases the viscosity of the mixture sufficiently to allow for injection.
- An active pharmaceutical ingredient may be added to the SAIB delivery vehicle to form SAIB solution or suspension formulations.
- the solvent differs from the matrix allowing the SAIB-drug or SAIB- drug-polymer mixtures to set up as an in situ forming depot.
- compositions may be administered to subjects either therapeutically or preventively.
- compositions are administered to a patient already suffering from cancer in an amount sufficient to cure or at least partially arrest the cancer and its complications.
- the composition should provide a quantity of the compound or agent sufficient to effectively treat the subject.
- the therapeutically effective amount for any particular subject will depend upon a variety of factors including: the cancer being treated and the severity thereof; the activity of the compound administered; the composition in which the compound is present; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of sequestration of the compound; the duration of the treatment; drugs used in combination or coincidental with the compound, together with other related factors well known in medicine.
- an effective dosage is expected to be in the range of about 0.0001 mg to about 1000 mg per kg body weight per 24 hours; typically, about 0.001 mg to about 750 mg per kg body weight per 24 hours; about 0.01 mg to about 500 mg per kg body weight per 24 hours; about 0.1 mg to about 500 mg per kg body weight per 24 hours; about 0.1 mg to about 250 mg per kg body weight per 24 hours; about 1.0 mg to about 250 mg per kg body weight per 24 hours.
- an effective dose range is expected to be in the range about 1.0 mg to about 200 mg per kg body weight per 24 hours; about 1.0 mg to about 100 mg per kg body weight per 24 hours; about 1.0 mg to about 50 mg per kg body weight per 24 hours; about 1.0 mg to about 25 mg per kg body weight per 24 hours; about 5.0 mg to about 50 mg per kg body weight per 24 hours; about 5.0 mg to about 20 mg per kg body weight per 24 hours; about 5.0 mg to about 15 mg per kg body weight per 24 hours.
- an effective dosage may be up to about 500 mg/m .
- an effective dosage is expected to be in the range of about 25 to about 500 mg/m , preferably about 25 to about 350 mg/m , more preferably about 25 to about 300
- the treatment would be for the duration of the disease state.
- the compounds of formula (I) may be used alone in the treatment of cancer, or alternatively in combination with radiotherapy and/or surgery and/or other therapeutic agents, for example chemotherapeutic agents and immunostimulatory agents, as part of a combination therapy.
- the compounds of formula (I) may sensitise cancer cells to other chemotherapeutic agents and/or radiotherapy.
- combination therapy and "adjunct therapy” are intended to embrace administration of multiple therapeutic agents in a sequential manner in a regimen that will provide beneficial effects and is intended to embrace administration of these agents in either a single formulation or in separate formulations.
- Combination therapy may involve the active agents being administered together, sequentially, or spaced apart as appropriate in each case.
- Combinations of active agents including compounds of the invention may be synergistic.
- co-administration of compounds of the formula (I) with other therapeutic agent(s) may be effected by a compound of the formula (I) being in the same unit dose form as the other therapeutic agent(s), or the compound of the formula (I) and the other therapeutic agent(s) may be present in individual and discrete unit dosage forms that are administered concurrently, sequentially or separately.
- Separate administration refers to administration of the compound of the formula (I) independently of the other therapeutic agent(s) at different time points. It may be the case that the compound of the formula (I) and the other therapeutic agent(s) are administered such that no overlap of measurable blood levels of the compound formula (I) and the other therapeutic agent(s) are present.
- sequence administration may be in any order as required, and may require an ongoing physiological effect of the first or initial agent to be current when the second or later agent is administered, especially where a cumulative or synergistic effect is desired.
- one or more compounds of formula (I) may be included in combination therapy with surgery and/or radiotherapy and/or one or more chemotherapeutic agents.
- chemotherapeutic agents that are currently in use, in clinical evaluation and in pre-clinical development, which could be selected for treatment of cancers in combination with compounds of the formula (I). Such agents fall into several major categories, namely, antibiotic-type agents, alkylating agents, anti-metabolite agents, hormonal agents, immunological agents, interferon-type agents and a category of miscellaneous agents. Alternatively, other chemotherapeutic agents, such as metallomatrix proteases (MMP) inhibitors may be used. Suitable agents which may be used in combination therapies include those listed, for example, in the Merck Index, An Encyclopaedia of Chemicals, Drugs and Biologicals, 12th Ed., 1996, the entire contents of which are incorporated herein by reference.
- MMP metallomatrix proteases
- compounds of the formula (I) When used in the treatment of solid tumours compounds of the formula (I) may be administered with one or more of the following chemotherapeutic agents: adriamycin, taxol, docetaxel, fluorouracil, melphalan, cisplatin, alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PROMACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins, TNP 470
- compositions comprising compounds of the formula (I) and vincristine or paclitaxel are synergistic. Accordingly, the present invention also relates to a combination comprising a compound of the general formula (I) and vincristine or paclitaxel.
- the present invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the general formula (I) vincristine or paclitaxel, and a pharmaceutically acceptable carrier, diluent or excipient.
- the present invention further relates to a kit of parts comprising a pharmaceutical composition of a compound of the general formula (I) and a pharmaceutical composition of vincristine or paclitaxel, wherein the compositions are intended for simultaneous, concurrent, separate or sequential use.
- the kit may further comprise instructions for administration of the compound of the general formula (I) and vincristine or paclitaxel to a subject.
- the present invention further relates to a method for the treatment of cancer in a subject in need thereof, the method comprising administration to the subject of a therapeutically effective amount of a compound of formula (I) and a therapeutically effective amount of vincristine or paclitaxel.
- the cancer may be any cancer as described herein.
- Administration of the compound of formula (I) and vincristine or paclitaxel may be simultaneous, concurrent, separate or sequential, as described above.
- the present invention further relates to use of a compound of formula (I) in the manufacture of a medicament for treating cancer, wherein the medicament is intended for administration with vincristine or paclitaxel.
- the cancer may be any cancer described herein.
- Administration of the compound of formula (I) and vincristine or paclitaxel may be simultaneous, concurrent, separate or sequential, as described above.
- Tosyl hydrazide (4.35 g, 23.3 mmol) was added to a stirred solution of 2,3-dimethyl-lH-indole-5-carbaldehyde (2.7 g, 16 mmol) in dry 1,4-dioxane (50 mL) at room temperature. The temperature was increased to 80 °C and maintained for 3 hours. The crude N'-((2,3-dimethyl-lH-indol-5-yl)methylene)-4- methylbenzenesulfonohydrazide in the reaction mixture was used without isolation or further purification.
- Tosyl hydrazide (663 mg, 3.5 mmol) was added to a stirred solution of 2,3- dimethyl-l-(2-methyl-3-(4-methylpiperazin-l-yl)propyl)-lH-indole-5-carbaldehyde (778 mg, 2.38 mmol) in dry 1,4-dioxane (30 mL) at room temperature, followed by the addition of glacial acetic acid (0.2 mL, cat.). The mixture was stirred at room temperature for 3 hours.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel using 5-10% methanol in dichloromethane as an eluent, to afford N-(3,5- dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl-l-(2-methyl-3-(4- methylpiperazin-l-yl)propyl)-lH-indol-5-yl)methyl)benzamide as a brown gummy oil (300 mg, 67%).
- reaction mixture was quenched with saturated NaHC0 3 , then extracted with 30% isopropyl alcohol in chloroform. The organic layer was washed with water and brine, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to obtain the crude product.
- Tosyl hydrazide (2.3 g, 12 mmol) was added to a stirred solution of 2,3- dimethyl-l-(2-methyl-3-(4-methylpiperazin-l-yl)propyl)-lH-indole-5-carbaldehyde (2.7 g, 8.2 mmol) in dry 1,4-dioxane (60 mL) at room temperature, followed by the addition of glacial acetic acid (0.7 mL, cat.). The mixture was stirred at room temperature for 3 hours. To this solution was added K 2 CO 3 (4.5 g, 33 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (2.2 g, 12 mmol).
- the reaction temperature was raised to 110 °C and maintained for 5 hours. After complete consumption of the starting material, the reaction mass was concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel, using 10% methanol in dichloromethane as an eluent, to obtain methyl 4-((2,3-dimethyl-l-(2-methyl-3-(4-methylpiperazin-l-yl)propyl)-lH- indol-5-yl)methyl)benzoate as a yellow solid (1.4 g, 38%).
- LCMS m/z 448.5 [M+H] + .
- BBr 3 (142 mL, 1.0 M in DCM) was added to a stirred solution of 5-methoxy- 2,3-dimethyl-lH-indole (10.0 g, 57.1 mmol) in dichloromethane (200 mL) at 0 °C. The temperature was maintained at 0-5 °C for 3 hours. After complete consumption of the starting material, the reaction mixture was basified with saturated NaHC0 3 then extracted with dichloromethane. The organic layer was washed with brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the organic layer was washed with water and brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel, using 13% ethyl acetate in petroleum ether as an eluent, to afford tert-butyX 5-hydroxy-2,3-dimethyl- lH-indole- 1-carboxylate as a yellow solid (11.2 g, 84%).
- the filtrate was diluted with water and extracted with dichloromethane.
- the organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel, using 3% ethyl acetate in petroleum ether as an eluent, to afford tert-butyX 5-(3-(methoxycarbonyl)phenoxy)-2,3-dimethyl- lH-indole-1 -carboxylate as a brown liquid (3.5 g, 46%).
- the organic layer was washed with chilled ammonium chloride solution and brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude product was purified by flash column chromatography, using 4% ethyl acetate in petroleum ether as an eluent, to afford methyl 3-((l-(3-chloropropyl)-2,3-dimethyl- lH-indol-5-yl)oxy)benzoate as a yellow liquid (600 mg, 20%).
- the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by flash column chromatography, using 5% methanol in dichloromethane as a eluent, to afford methyl 3-((2,3-dimethyl-l-(3-(4-methylpiperazin-l-yl)propyl)-lH-indol-5- yl)oxy)benzoate (380 mg, 44%).
- the organic layer was washed with water and brine, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel, using ethyl acetate and 5% methanol in dichloromethane as an eluent, to afford N-(3,5-dimethoxy-4-(pyridin-4-yl)phenyl)-3-((2,3-dimethyl- 1-(3-(4- methylpiperazin-l-yl)propyl)-lH-indol-5-yl)oxy)benzamide as a brown solid (50 mg, 34%).
- the organic layer was washed with chilled ammonium chloride solution, then brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compounds was purified by column chromatography on 100-200 mesh silica gel using petroleum ether as an eluent, to afford 5-bromo-l-(3-chloro-2- methylpropyl)-2,3-dimethyl-lH-indole as a yellow liquid (6 g, crude).
- the filtrate was diluted with water and extracted with dichloromethane.
- the organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel, using 10% ethyl acetate in petroleum ether as an eluent, to afford tert-butyX 5-(4-(methoxycarbonyl)phenoxy)-2,3-dimethyl- lH-indole-1 -carboxylate as an off white solid (6.0 g, 66%).
- the organic layer was washed with water and brine, then dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to obtain the crude product.
- the crude compound was purified by column chromatography on 100-200 mesh silica gel, using 4% methanol in dichloromethane as an eluent, to afford N-(3,5-dimethoxy-4-(pyridin- 4-yl)phenyl)-4-((2,3-dimethyl-l-(3-(4-methylpiperazin-l-yl)propyl)-lH-indol-5- yl)oxy)benzamide as a brown solid (100 mg, 44%).
- the organic layer was washed with brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to give the crude product.
- the crude compound was purified by flash column chromatography using 5% ethyl acetate in petroleum ether as an eluent to afford 5-bromo- l-(3-chloropropyl)-2,3-dimethyl-lH- indole as a pink solid (2.6 g, 39%).
- reaction mixture was heated to 100 °C for 12 hours in a sealed tube. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The organic layer was washed with water and brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by prep-TLC using 5% methanol in dichloromethane as an eluent to afford N-(4-(lH-imidazol-l-yl)-3,5- dimethoxyphenyl)-3-((2,3-dimethyl-l-(3-(4-methylpiperazin-l-yl)propyl)-lH-indol- 5-yl)amino)benzamide as a brown solid (80 mg, 23%).
- reaction mixture was heated to 100 °C for 12 hours in a sealed tube. After complete consumption of the starting material, the reaction mixture was diluted with ethyl acetate and filtered through a plug of Celite. The organic layer was washed with brine solution, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to afford the crude product.
- the crude compound was purified by prep-TLC, using 5% methanol in dichloromethane as an eluent to afford 4-((2,3-dimethyl-l-(3-(4-methylpiperazin-l-yl)propyl)-lH-indol-5- yl)amino)-N-(4'-fluoro-2,6-dimethoxy-[l, -biphenyl]-4-yl)benzamide as a brown gummy solid (120 mg, 34%).
- reaction mixture was quenched with saturated NaHC0 3 , then extracted with 30% isopropyl alcohol in chloroform. The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 and concentrated under reduced pressure to obtain the crude product.
- SK-N-SH neuroblastoma cells were seeded at 30 x 10 cells/well in a in a volume of 1000 ⁇ ⁇ with complete media onto a 12 well plate containing 19 mm coverslips and left to plate down for 24 hours prior to treatment. Cells were then treated with 0, 2.5 and 5 ⁇ of the test compounds.
- each cell line was then exposed to various concentrations of each respective analogue (30, 10, 3, 1, 0.3 and 0.1 ⁇ ), cultured for a further 72 h and exposed to cell-titre luminescent reagent (100 ⁇ / ⁇ ) for a further 30 min.
- Luminescence was captured using an En Vision multilabel reader and the data for each analogue concentration compared against no treatment control.
- Cell viability was normalized to control (vehicle alone) and dose-response curves, and half maximal effective concentration (EC 50 ) values were determined using Graph Pad Prism 6 (nonlinear regression sigmoidal dose-response variable slope).
- SHEP and SK-Mel-28 cell lines were maintained as monolayers in Dulbeccos Modified Eagles medium (DMEM-Invitrogen) supplemented with 10% fetal bovine serum (FBS) and grown at 37 °C in a humidified atmosphere with 5% C0 2 .
- DMEM-Invitrogen Dulbeccos Modified Eagles medium
- FBS fetal bovine serum
- 2 x 10 J cells were plated into 96 well plates and treated with serial dilutions of drug (1:2 starting concentration of 200 ⁇ ) and viability measured after 48 hours using a standard MTS assay.
- Stock solutions (10 mM) were prepared by dissolving compounds in 100% sterile DMSO. Vincristine and paclitaxel were further diluted to 0.1 mM for experiments. Small aliquots (20 ⁇ ) were prepared and stored at -30 °C under minimum light. Stock solutions were defrosted once only for each experiment.
- the A549 and A375 cells were cultured in DMEM cell culture medium supplemented with 10% (v/v) FBS and the DU145 cells were cultured in RPMI cell culture medium supplemented with 10% (v/v) FBS. All cell lines were cultured in the absence of antibiotics for no more than 10 passages. The cells were harvested at -80% confluence by trypsinisation (passage +111 (A549), passage +20 (A375) and passage 8 (DU145)). Cells were then washed, counted and plated in 384-well plates.
- test compounds positive control (20 ⁇ Thonzonium bromide, 100% kill) and vehicle only (0.4% DMSO) were added into wells of each assay plate using a Tecan HP D300 Digital Dispenser in technical triplicate under minimum light.
- metabolic activity was detected by addition of 10% (v/v) alamar blue reagent to each assay well using a Multidrop Combi (Thermo Scientific) and determined by measurement of fluorescence intensity (excitation 555 nm, emission 585 nm) using an EnSpire (Perkin Elmer) plate reader. Readings were performed at 0 hour (background) and after 6 hours alamar blue incubation at 37 °C.
- IC 50 concentrations of the compounds together with vincristine and paclitaxel as single agents against all cell lines were determined for a 72 h drug exposure using the growth inhibition assay with alamar blue readout in triplicate in two independent experiments. Each drug was tested as a 10-point concentration series with two-fold serial dilutions of each drug. The concentration series for the compounds for all cell lines tested was 20, 10, 5, 2.5, 1.25, 0.625, 0.3125, 0.156, 0.078 and 0.039 ⁇ for the two independent experiments. The concentration series for vincristine and paclitaxel was 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.781, 0.391 and 0.195 nM.
- Thonzonium bromide (20 ⁇ ) and 0.4% DMSO were used as positive and vehicle controls, respectively.
- the IC50 value was calculated by derivation of the best-fit line using a sigmoidal dose response model (Activity Base Software Suite, IDBS). Drug combination screen
- Each drug combination was tested against A375, A549 and DU145 cells using a 6x6 dose matrix with 2-fold dilution steps based on the calculated IC50 values using the growth inhibition assay with 72h drug exposure in a 384-well format.
- the two drugs in each combination matrix were dispensed using a Tecan HP D300 Digital Dispenser.
- the layout of each screening plate is shown in Figure 3.
- Assays were performed in triplicate for each drug combination (ATM/vincristine and ATM/paclitaxel combinations). Synergistic drug interactions were calculated from the averaged cell viability data using the methodology described below.
- IDBS Activity Base software suite
- IC 50 concentrations were calculated by derivation of the best-fit line using a sigmoidal dose response model with technical triplicate data points.
- the Bliss additivism model was used to calculate a predicted combined response C to two single agents with responses A and B (using GI values), as follows:
- the IC 50 concentrations of the compounds, vincristine and paclitaxel as single agents were determined against A375, A549 and DU145 cells using the growth inhibition assay with alamar blue cell viability readout.
- the data is listed as IC 50 mean from technical triplicates for two independent experiments in Table 3.
- the averaged IC 50 concentrations for the single agents from both runs were then used to generate the 6x6 dose matrices in the synergy experiment.
- the compounds were tested in combination with vincristine and paclitaxel as a 6x6 dose matrix in triplicate for each cell line.
- Synergy scores for each drug combination were calculated by the Bliss-independence model.
- the max synergy and total synergy scores for each combination in all cell lines tested are listed in Tables 4- 6 below.
- Max synergy is the highest individual synergy score for each combination matrix
- Total synergy is the summation of each individual synergy score for the matrix.
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- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne de façon générale des indoles fonctionnalisés et substitués, leur préparation et leur utilisation dans le traitement de maladies prolifératives telles que le cancer.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US201562167182P | 2015-05-27 | 2015-05-27 | |
US62/167,182 | 2015-05-27 | ||
US201662278886P | 2016-01-14 | 2016-01-14 | |
US62/278,886 | 2016-01-14 |
Publications (1)
Publication Number | Publication Date |
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WO2016187667A1 true WO2016187667A1 (fr) | 2016-12-01 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/AU2016/050407 WO2016187667A1 (fr) | 2015-05-27 | 2016-05-26 | Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux |
Country Status (2)
Country | Link |
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TW (1) | TW201710251A (fr) |
WO (1) | WO2016187667A1 (fr) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110229091A (zh) * | 2019-06-21 | 2019-09-13 | 天津科技大学 | 具有白三烯a4水解酶抑制作用的1,5-二取代吲哚衍生物及应用 |
WO2020097012A1 (fr) | 2018-11-06 | 2020-05-14 | Fmc Corporation | Tolyles substitués utilisés en tant que fongicides |
WO2021226234A1 (fr) | 2020-05-06 | 2021-11-11 | Fmc Corporation | Fongicides à base de tolyle substitués et leurs mélanges |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2001025220A1 (fr) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Inhibiteurs de triazine kinase |
WO2002083653A1 (fr) * | 2001-04-11 | 2002-10-24 | Amgen Inc. | Derives d'acrylamide de triazinyle utilises comme inhibiteur de kinase |
US20090233910A1 (en) * | 2005-04-15 | 2009-09-17 | Cerep | Npy antagonists, preparation and uses |
WO2015074124A1 (fr) * | 2013-11-25 | 2015-05-28 | Novogen ltd | Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux |
-
2016
- 2016-05-26 WO PCT/AU2016/050407 patent/WO2016187667A1/fr active Application Filing
- 2016-05-26 TW TW105116520A patent/TW201710251A/zh unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001025220A1 (fr) * | 1999-10-07 | 2001-04-12 | Amgen Inc. | Inhibiteurs de triazine kinase |
US20040116388A1 (en) * | 1999-10-07 | 2004-06-17 | Amgen Inc. | Kinase inhibitors |
WO2002083653A1 (fr) * | 2001-04-11 | 2002-10-24 | Amgen Inc. | Derives d'acrylamide de triazinyle utilises comme inhibiteur de kinase |
US20090233910A1 (en) * | 2005-04-15 | 2009-09-17 | Cerep | Npy antagonists, preparation and uses |
WO2015074124A1 (fr) * | 2013-11-25 | 2015-05-28 | Novogen ltd | Indoles fonctionnalisés et substitués utilisés en tant qu'agents anti-cancéreux |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020097012A1 (fr) | 2018-11-06 | 2020-05-14 | Fmc Corporation | Tolyles substitués utilisés en tant que fongicides |
CN110229091A (zh) * | 2019-06-21 | 2019-09-13 | 天津科技大学 | 具有白三烯a4水解酶抑制作用的1,5-二取代吲哚衍生物及应用 |
CN110229091B (zh) * | 2019-06-21 | 2022-11-22 | 天津科技大学 | 具有白三烯a4水解酶抑制作用的1,5-二取代吲哚衍生物及应用 |
WO2021226234A1 (fr) | 2020-05-06 | 2021-11-11 | Fmc Corporation | Fongicides à base de tolyle substitués et leurs mélanges |
Also Published As
Publication number | Publication date |
---|---|
TW201710251A (zh) | 2017-03-16 |
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