WO2014008592A1 - Combinaisons comprenant des composés diamidine et des inhibiteurs de parp à utiliser dans le traitement du cancer - Google Patents

Combinaisons comprenant des composés diamidine et des inhibiteurs de parp à utiliser dans le traitement du cancer Download PDF

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WO2014008592A1
WO2014008592A1 PCT/CA2013/050509 CA2013050509W WO2014008592A1 WO 2014008592 A1 WO2014008592 A1 WO 2014008592A1 CA 2013050509 W CA2013050509 W CA 2013050509W WO 2014008592 A1 WO2014008592 A1 WO 2014008592A1
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cancer cells
cells
cancer
pharmaceutically acceptable
acceptable salt
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PCT/CA2013/050509
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Terry Chow
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Oncozyme Pharma Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to combinations of chemotherapeutic agents for treating cancer.
  • PARP is a nuclear enzyme that detects DNA damage, binds to DNA single or double strand breaks, and then uses NAD+ as a substrate to form nicotinamide and ADPribose. Poly(ADP-ribosylation) of the PARP then function in DNA repair by modifying structural proteins proximal to DNA strand breaks, facilitating the opening of the condensed chromatin structure, which is required for the recruitment of DNA repair complexes. Nicotinamide, therefore, function as an NAD+ precursor and a substrate for PARP.
  • Early forms of PARP inhibitor thus are derivatives of Niacin and quinolinate (i.e. 3-methozybenzamide and 1 ,5-isoquinolinediol) and provided a chemical base for generating new PARP inhibitors.
  • Diamidine compounds such as pentamidine, belong to the class of small chemical entities known as diamidines. Diamidines intercalate at the minor grove of the DNA structure and as well as demonstrated to inhibit several proteins; among of which is the endo-exonuclease, a DNA double stranded break repair protein epitasis to the RAD52. Pentamidine has been shown to bind to the endo-exonuclease.
  • One aspect of the invention includes combinations comprising a therapeutically effective amount of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for inhibiting the proliferation of cancer cells in a patient in need thereof.
  • One aspect of the invention includes combinations comprising a therapeutically effective amount of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for treating cancer in a patient in need thereof.
  • One aspect of the invention includes the use of a therapeutically effective amount of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for inhibiting the proliferation of cancer cells in a patient in need thereof.
  • One aspect of the invention includes the use of a therapeutically effective amount of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for treating cancer in a patient in need thereof.
  • One aspect of the invention includes a method for inhibiting the proliferation of cancer cells in a patient in need thereof comprising administering a therapeutically effective amount of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for inhibiting the proliferation of cancer cells in a patient in need thereof.
  • One aspect of the invention includes a method for treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for inhibiting the proliferation of cancer cells in a patient in need thereof.
  • One aspect of the invention includes a pharmaceutical composition
  • a pharmaceutical composition comprising
  • One aspect of the invention includes a pharmaceutical combination comprising (1 ) at least one diamidine compound and (2) at least one PARP inhibitor.
  • Figure 1 Effect of Saline, Pentamidine (103), Veliparib, Pentamiine (103)+Veliparib on the growth of ovarian tumor in mouse human xenograft.
  • Figure 2 Effect of Saline, Pentamidine (103), Veliparib, Pentamidine (103)+Veliparib on body weight [14]
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the diamidine compound is an aromatic diamidine compound.
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the diamidine compound is pentamidine.
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the diamidine compound is pentamidine bis(2- hydroxyethanesulfonate).
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the PARP inhibitor is NU1025, ABT-888 (Veliparib), Olaparib (was AZD-2281 ), CEP 9722, MK4827, AG014699, Iniparib (previously BSI 201 ), LT-673, 3-aminobenzamide or E7016.
  • the PARP inhibitor is NU1025, ABT-888 (Veliparib), Olaparib (was AZD-2281 ), CEP 9722, MK4827, AG014699, Iniparib (previously BSI 201 ), LT-673, 3-aminobenzamide or E7016.
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the diamidine compound is pentamidine bis(2- hydroxyethanesulfonate) and wherein the PARP inhibitor is NU1025, ABT-888 (Veliparib), Olaparib (was AZD-2281 ), CEP 9722, MK4827, AG014699, Iniparib (previously BSI 201 ), LT-673, 3-aminobenzamide or E7016.
  • the diamidine compound is pentamidine bis(2- hydroxyethanesulfonate) and wherein the PARP inhibitor is NU1025, ABT-888 (Veliparib), Olaparib (was AZD-2281 ), CEP 9722, MK4827, AG014699, Iniparib (previously BSI 201 ), LT-673, 3-aminobenzamide or E7016.
  • cancer cells are squamous cell carcinoma cells, larger cell carcinoma of the lymph node cells, breast cancer cells, colon cancer cells, lung carcinoma cells, melanoma cells, pancreatic cancer cells, leukemia cells, non-small cell lung cancer cells, colon cancer cells, central nervous system (CNS) cancer cells, ovarian cancer cells, renal cancer cells or prostate cancer cells.
  • CNS central nervous system
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the cancer cells are pancreatic cancer cells, colon cancer cells, breast cancer cells or ovarian cancer cells.
  • the cancer is squamous cell carcinoma, larger cell carcinoma of the lymph node, breast cancer, colon cancer, lung carcinoma, melanoma, pancreatic cancer, leukemia, non-small cell lung cancer, colon cancer, central nervous system (CNS) cancer, ovarian cancer, renal cancer or prostate cancer.
  • One aspect of the invention includes combinations, compositions, uses or methods as described herein wherein the cancer is pancreatic cancer, colon cancer, breast cancer or ovarian cancer.
  • One aspect of the present invention is a method of inhibiting the proliferation of cancer cells comprising administering to a patient in need thereof (1 ) at least one diamidine compound and (2) at least one PARP inhibitor.
  • the agents can be given either separately, for example on consecutive days, or together.
  • One aspect of the present invention is the use of (1 ) at least one diamidine compound and (2) at least one PARP inhibitor for inhibiting the proliferation of cancer cells comprising in a patient in need thereof .
  • the method or use inhibits the proliferation of cancer cells and tumor growth.
  • a pharmaceutical composition for inhibiting the proliferation of cancer cells and/or tumor growth that comprises a combination of the compounds above.
  • the invention relates to the surprising discovery that the combinations are synergistic.
  • the cancer cells are squamous cell carcinoma cells, larger cell carcinoma of the lymph node cells, breast cancer cells, colon cancer cells, lung carcinoma cells, melanoma cells, pancreatic cancer cells, leukemia cells, non-small cell lung cancer cells, colon cancer cells, central nervous system (CNS) cancer cells, ovarian cancer cells, renal cancer cells or prostate cancer cells.
  • the cancer cells are pancreatic cancer cells, colon cancer cells, breast cancer cells or ovarian cancer cells.
  • the diamidine compounds are endo-exonuclease inhibitors.
  • the combinations are believed to operate in view of the inhibition of endo-exonuclease activity by diamidine compounds such as pentamidine.
  • diamidine compounds such as pentamidine.
  • pentamidine More endo-exonuclease activity inhibitors can also be used together with or in place of pentamidine, such as distamycin A and berenil.
  • Such inhibition prevents repair of double-breaks induced directly or indirectly by the mentioned DNA break-inducing agents and/or naturally occurring double strand breaks during cell division and replication; a phenomenon known to be exaggerated in cancer cells.
  • the mentioned DNA break-inducing agents can cause double strand breaks directly or can cause single strand breaks that progress to double strand breaks. This is a common occurrence in biological systems.
  • the endo-exonuclease inhibitors such as pentamidine prevent double break repair and thus enhance anticancer effects.
  • diamidine compounds are represented by the formula:
  • R is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or other organic moiety with 2 to 12 carbons.
  • R is substituted or unsubstituted Ci-6 alkyl.
  • R is substituted or unsubstituted C3-5 alkyl.
  • R is a substituted or unsubstituted C 5 alkyl.
  • R is unsubstituted d -6 alkyl, C 3-5 alkyl or C 5 alkyl.
  • the diamidine compound is propamidine, butamidine, pentamidine, hexamidine, heptamidine, and so on, or stilbamidine, furamidine, pafuramidine, or 4,4'(diazoamino)dibenzamidine diaceturate.
  • the diamidine compound is propamidine, pentamidine or stilbamidine.
  • Pentamidine refers to the free compound or to the compound in salt form, e.g., as the bis(2-hydroxyethanesulfonate) or isethionate salt, mesylate, gluconate or any other pharmaceutically acceptable salt.
  • Pentamidine is represented by the formula:
  • PARP inhibitor refers to an inhibitor or antagonist of Poly(ADP-ribose) polymerases (PARP 1 and/or PARP2 ) activity.
  • a PARP inhibitor or antagonist is a compound that selectively inhibits the activity of PARP and refers to a compound that when administered to a subject the PARP activity within the subject is altered, preferably reduced.
  • a drug also able to decrease PARPs expression is also considered as PARP inhibitor.
  • PARP is activated when Poly ADP ribose polymer is increased.
  • a prodrug of a PARP inhibitor is administered to a subject that is converted to the compound in vivo where it inhibits PARP.
  • the PARP inhibitor may be any type of compound.
  • the compound may be a small organic molecule or a biological compound such as an antibody or an enzyme.
  • Example of PARP inhibitors are described in Penning, Current Opinion In Drug Discovery & Development 2010 13 (5): 577-586. A person skilled in the art can easily determine whether a compound is capable of inhibiting PARP activity. Assays for evaluating PARP activity are for example, described in Poly(ADP-ribose) (PAR) polymer is a death signal (Andrabi SA et al., 2006). PARP inhibition may be determined using conventional methods, including for example dot blots (Affar EB et al., Anal Biochem.
  • Examples of compounds which are known PARP inhibitors and which may be used include compounds and derivatives thereof from the class of Nicotinamides, Benzamides, Isoquinolinones, Dihydroisoquinolinones, Benzimidazoles, indoles, Phthalazin-1 (2H)-ones, quinazolinones, Isoindolinones, Phenanthridines, phenanthhdinones, Benzopyrones, Unsaturated hydroximic acid derivatives and Pyridazines.
  • Nicotinamides such as 5-methyl nicotinamide and 0-(2-hydroxy-3-piperidino- propyl)-3-carboxylic acid amidoxime, and analogues and derivatives thereof.
  • Benzamides including 3-substituted benzamides such as 3-aminobenzamide, 3-hydroxybenzamide, 3-nitrosobenzamide, 3-methoxybenzamide and 3- chloroprocainamide, and 4-aminobenzamide, 1 , 5-di[(3- carbamoylphenyl)aminocarbonyloxy] pentane, and analogues and derivatives thereof.
  • Isoquinolinones and Dihydroisoquinolinones including 2H-isoquinolin-1 -ones, 3H-quinazolin-4-ones, 5-substituted dihydroisoquinolinones such as 5-hydroxy dihydroisoquinolinone, 5-methyl dihydroisoquinolinone, and 5-hydroxy isoquinolinone, 5-amino isoquinolin-1 -one, 5-dihydroxyisoquinolinone, 3, 4 dihydroisoquinolin-1 (2H)- ones such as 3, 4 dihydro-5-methoxy-isoquinolin-1 (2H)-one and 3, 4 dihydro-5-methyl- 1 (2H)isoquinolinone, isoquinolin-1 (2H)-ones, 4,5-dihydro-imidazo[4,5, 1 -ij]quinolin-6- ones, 1 , 6,-naphthyridine-5(6H)-ones, 1 ,
  • Benzimidazoles and indoles including benzoxazole-4-carboxamides, benzimidazole-4-carboxamides, such as 2-substituted benzoxazole 4-carboxamides and 2-substituted benzimidazole 4-carboxamides such as 2-aryl benzimidazole 4- carboxamides and 2-cycloalkylbenzimidazole-4-carboxamides including 2-(4- hydroxphenyl) benzimidazole 4-carboxamide, quinoxalinecarboxamides, imidazopyridinecarboxamides, 2-phenylindoles, 2-substituted benzoxazoles, such as 2- phenyl benzoxazole and 2-(3-methoxyphenyl) benzoxazole, 2-substituted benzimidazoles, such as 2-phenyl benzimidazole and 2-(3-methoxyphenyl) benzimidazole, 1 , 3, 4, 5 te
  • Phthalazin-1 (2H)-ones and quinazolinones such as 4-hydroxyquinazoline, phthalazinone, 5-methoxy-4-methyl-1 (2) phthalazinones, 4-substituted phthalazinones, 4-(1 -piperazinyl)-1 (2H)-phthalazinone, tetracyclic benzopyrano[4, 3, 2-de] phthalazinones and tetracyclic indeno [1 , 2, 3-de] phthalazinones and 2-substituted quinazolines, such as 8-hydroxy-2-methylquinazolin-4-(3H) one, tricyclic phthalazinones and 2-aminophthalhydrazide, and analogues and derivatives thereof.
  • Phenanthridines and phenanthridinones such as 5[H]phenanthridin-6-one, substituted 5[H] phenanthridin-6-ones, especially 2-, 3- substituted 5[H] phenantridin-6- ones and sulfonamide/carbannide derivatives of 6(5H)phenanthridinones, thieno[2, 3- c]isoquinolones such as 9-annino thieno[2, 3-c]isoquinolone and 9-hydroxythieno[2, 3- c]isoquinolone, 9-methoxythieno[2, 3-c]isoquinolone, and N-(6-oxo-5, 6- dihydrophenanthridin-2-yl]-2-(N,N-dimethylannino ⁇ acetannide, substituted 4,9- dihydrocyclopenta[lmn]phenanthridine-5-ones, and analogues and derivatives thereof.
  • Benzopyrones such as 1 , 2-benzopyrone, 6-nitrosobenzopyrone, 6-nitroso 1 , 2-benzopyrone, and 5-iodo-6-aminobenzopyrone, and analogues and derivatives thereof.
  • [54] 1 1 Other compounds such as caffeine, theophylline, and thymidine, and analogues and derivatives thereof.
  • PARP inhibitors include NU1025, ABT-888 (Veliparib), Olaparib (was AZD-2281 ), CEP 9722, MK4827, AG014699, Iniparib (previously BSI 201 ), LT-673, 3-aminobenzamide and E7016.
  • the PARP inhibitor is Veliparib and is represented by the formula:
  • the PARP inhibitor is Oliparib and is represented by the formula:
  • the PARP inhibitor is Iniparib and is represented by the formula:
  • One aspect of the invention include combinations and compositions comprising (1 ) at least one diamidine compound, (2) at least one PARP inhibitor in synergistic amounts.
  • One aspect of the invention include combinations and compositions comprising (1 ) at least one diamidine compound, (2) at least one PARP inhibitor in which the weight ratio of the at least one diamidine compound to the at least one PARP inhibitor is between about 0.5:20 and about 20:0.5; between about 10:0.5 and about 0.5: 10; between about 5:0.5 and about 0.5:5; between about 0.5: 1 and about 1 :0.5.
  • One aspect of the invention include combinations and compositions comprising (1 ) at least one diamidine compound, (2) at least one PARP inhibitor and (3) at least one additional further anti-cancer agent for inhibiting the proliferation of cancer cells or for the treatment of cancer in a patient in need thereof.
  • One aspect of the invention include method and uses thereof of combination and composition comprising (1 ) at least one diamidine compound, (2) at least one PARP inhibitor and (3) at least one additional further anti-cancer agents for inhibiting the proliferation of cancer cells or for the treatment of cancer in a patient in need thereof.
  • the further agent include but are not limited to cisplatin, mitomycin C, melphalan, carmustine, adriamycin, paclitaxel, docetaxel, 5-fluorouracil, bevacizumab, cetuximab, capecitabine, folinic acid (also known as leucovorin), ionizing irradiation, bleomycin, carboplatin, oxaliplatin, irinotocan, etoposide, temozolomide, doxorubicin and/or gemcitabine.
  • cisplatin mitomycin C, melphalan, carmustine, adriamycin, paclitaxel, docetaxel, 5-fluorouracil, bevacizumab, cetuximab, capecitabine, folinic acid (also known as leucovorin), ionizing irradiation, bleomycin, carboplatin, oxaliplatin,
  • the further agent is carboplatin and/or gemcitabine.
  • One aspect of the invention include combinations and compositions comprising (1 ) at least one diamidine compound, (2) at least one PARP inhibitor and (3) at least one additional further anti-cancer agents in synergistic amounts.
  • combinations and compositions further comprise at least one additional further anti-cancer agents in which the weight ratio of the at least one diamidine compound to the at least one additional further anti-cancer agents is between about 0.5:20 and about 20:0.5; between about 10:0.5 and about 0.5: 10; between about 5:0.5 and about 0.5:5; between about 0.5: 1 and about 1 :0.5.
  • One aspect of the invention includes methods, uses, combinations and compositions as described herein wherein the compounds are used sequentially or simultaneously.
  • patient means human.
  • terapéuticaally acceptable amount refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought be a researcher or clinician.
  • treatment includes palliative, restorative, and preventative treatment of a patient.
  • palliative treatment refers to treatment that eases or reduces the effect or intensity of a condition in a subject without curing the condition.
  • preventative treatment refers to treatment that prevents the occurrence of a condition in a patient.
  • restorative treatment refers to treatment that halts the progression of, reduces the pathologic manifestations of, or entirely eliminates a condition in a patient.
  • alkyl represents a linear, branched or cyclic hydrocarbon moiety.
  • alkenyl and alkynyl represent a linear, branched or cyclic hydrocarbon moiety which has one or more double bonds or triple bonds in the chain.
  • alkyl, alkenyl, and alkynyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, neohexyl, allyl, vinyl, acetylenyl, ethylenyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, hexatrienyl, heptenyl, heptadienyl, heptatrienyl, octenyl, octadienyl, octat
  • alkyl alkenyl
  • alkynyl can be optionally substituted such as in the case of haloalkyls in which one or more hydrogen atom is replaced by a halogen, e.g. an alkylhalide.
  • haloalkyls include but are not limited to trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, trifluoroethyl, difluoroethyl, fluoroethyl, trichloroethyl, dichloroethyl, chloroethyl, chlorofluoromethyl, chlorodifluoromethyl, dichlorofluoroethyl.
  • R a -C(0)R a -C(0)OR a
  • -S0 2 NR a R b -NR a S0 2 R b
  • R a -R j are each independently H, Ci -4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl.
  • the "alkyl,” “alkenyl,” and “alkynyl” can also be optionally substituted by -OCONR e R f .
  • heterocycle represents an optionally substituted, non-aromatic, saturated or partially saturated wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (0), sulfur (S) or nitrogen (N).
  • Heterocycles may be monocyclic or polycyclic rings.
  • a 3-12 member heterocycle is an optionally substituted, non-aromatic, saturated or partially saturated cyclic moiety having 3-12 ring atoms wherein at least one ring atom is a heteroatom selected from oxygen (0), sulfur (S) or nitrogen (N).
  • Examples include but are not limited to azetidinyl, dioxolanyl, morpholinyl, morpholino, oxetanyl, piperazinyl, piperidyl, piperidino, cyclopentapyrazolyl, cyclopentaoxazinyl, cyclopentafuranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl dioxyde, thiazolinyl, oxazolinyl, pyranyl, thiopyranyl, aziridinyl, azepinyl, dioxazepinyl, diazepinyl, oxyranyl, oxazinyl, pyrrolidinyl, thiopyranyl, thiolane, pyr
  • heterocycle- alkyl represents an optionally substituted heterocycle group attached to the adjacent atom by an alkyl, alkenyl, or alkynyl group. It is understood that in a 5-18 member heterocycle-alkyl moiety, the term “5-18 member” represents the total number of ring atoms present in the heterocycle moiety and carbon atoms present in the alkyl, alkenyl or alkynyl portion.
  • aryl represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e., may be monocyclic or polycyclic), and which where indicated may be optionally substituted with one or more substituents. Examples include but are not limited to phenyl, tolyl, dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyl.
  • heteroaryl represents an optionally substituted aromatic cyclic moiety wherein said cyclic moiety is interrupted by at least one heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N). Heteroaryls may be monocyclic or polycyclic rings. For example, a 5-12 member heteroaryl is an optionally substituted, aromatic cyclic moiety having 5-12 ring atoms wherein at least one ring atom is a heteroatom selected from oxygen (O), sulfur (S) or nitrogen (N).
  • Examples include but are not limited to - dithiadiazinyl, furanyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, dioxazole, oxatriazole, oxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyridyl, pyrazolyl, pyrrolyl, thiatriazolyl, tetrazolyl, thiadiazolyl, triazolyl, thiazolyl, thienyl, tetrazinyl, thiadiazinyl, triazinyl, thiazinyl, furoisoxazolyl, imidazothiazolyl, thienoisothiazolyl, thienothiazolyl, imidazopyrazolyl, pyrrolopyrrolyl, thienothienyl, thiadiazolopyrimidinyl,
  • heteroarylkyl represents an optionally substituted heteroaryl group attached to the adjacent atom by an alkyl, alkenyl, or alkynyl group.
  • alkoxy represents an alkyl, alkenyl or alkynyl moiety, respectively, which is covalently bonded to the adjacent atom through an oxygen atom. Examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, isohexyloxy, trifluoromethoxy and neohexyloxy.
  • aryloxy represent an aryl moiety substituted with an oxygen, wherein the point of attachement to the molecule it substitutes is on the oxygen.
  • aryl represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e., may be monocyclic or polycyclic), and which where indicated may be optionally substituted with one or more substituents. Examples include but are not limited to phenyl, tolyl, dimethylphenyl, aminophenyl, anilinyl, naphthyl, anthryl, phenanthryl or biphenyl.
  • the present invention is intended to encompass all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified since it is well known in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
  • salts compounds recited herein are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Salts derived from amino acids are also included (e.g.
  • Salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium) and alkaline earth metals (e.g. calcium, magnesium).
  • alkali metals e.g. sodium, lithium, potassium
  • alkaline earth metals e.g. calcium, magnesium.
  • polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day. While it is possible that, for use in therapy, the compounds may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical composition.
  • the invention thus further provides a pharmaceutical combination or composition of the compounds as described herein or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compositions may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
  • the compounds may also be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are for example presented as unit dose suppositories.
  • Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds or combinations may be used as a liquid spray or dispersible powder or in the form of drops. Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.
  • the compounds or combinations are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds or combinations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • an acceptable carrier means a vehicle for the combinations and compounds described herein that can be administered to a subject without adverse effects.
  • Suitable carriers known in the art include, but are not limited to, gold particles, sterile water, saline, glucose, dextrose, or buffered solutions.
  • Carriers may include auxiliary agents including, but not limited to, diluents, stabilizers (i.e., sugars and amino acids), preservatives, wetting agents, emulsifying agents, pH buffering agents, viscosity enhancing additives, colors and the like.
  • pentamidine is intravenous.
  • Typical doses for each of the agents for use in this invention are in the normal ranges conventionally known for each known agent used individually to treat cancer.
  • typical daily doses are 2-8 mg/kg body weight in humans.
  • the dose of pentamidine can be lower than the typical doses.
  • pentamidine in addition, the amount found in the urine does not increase significantly with repeated dosing. This means that when pentamidine is given repeatedly, it accumulates in body tissues. Pentamidine was detected in tissue 25 days after final dose. Hence, pentamidine is only slowly released from tissue. It is also widely distributed in tissue (Goa, K.L., Campoli-Richards, D.M.;Drugs (1987), 33, 242). Thus, pentamidine can be administered to the patient before, after, or concurrently with other chemotherapy since its effectiveness depends on its distribution to and persistence in body tissues over long periods.
  • a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, for example, in the range of 0.5 to 60 mg/kg/day, or, for example, in the range of 1 to 20 mg/kg/day.
  • the PARP inhibitor is conveniently administered in unit dosage form; for example containing 5 to 2000 mg, 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
  • Pentamidine used in these experiments is pentamidine bis(2- hydroxyethanesulfonate) salt.
  • Cell lines The cell lines HT29, MCF7, and H460 were obtained from ATCC. The cellswere grown in RPMI media supplemented with 10% FCS at 37 in a humidified incubator with 5% C02.
  • MTT 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyltertrazolim bromide
  • MTT is a tetrazolium salt cleaved by mitochondrial dehydrogenases of living cells. Cleavage converts yellow, water soluble MTT to an insoluble, purple formazan crystal.
  • the crystals can be solubilized with a 50% ⁇ , ⁇ -dimethylformamide (vol/vol), 20% SDS (wt/vol) solution (pH4.7), and absorbance determined at a wavelength of 570 nm.
  • Dead cells will not cleave MTT and uncleaved MTT is not detectable at this wavelength.
  • the amount of MTT that is cleaved increases with increasing cell numbers, and decreases as a result of cell cytotoxicity (Niks and Otto 1990 ("Towards an optimized MTT assay," J. Immunol. Methods. 130, 149-151 ) Hussain et al. 1993 ("A new approach for measurement of cytotoxicity using colorimetric assay," J. Immunol. Methods. 160, 89-96).
  • Results presented in Tables 1 -3 indicate that PENTAMIDINE BIS(2- HYDROXYETHANESULFONATE), when used in combination with any one of the three PARP inhibitors, on any of the three cell lines studied, has a synergistic cytotoxic activity and/or potentiates the effect of the PARP inhibitor.
  • the % inhibition is higher than the anticipated additive killing action of the individual drugs. For example, in Table 1 , killing by Iniparib (42 ⁇ ) alone at 0.75% + PENTAMIDINE BIS(2-HYDROXYETHANESULFONATE) (33 ⁇ ) alone at 25% would yield an additive effect of approximately 25.75%.
  • the cells were grown in RPMI media supplemented with 10% FCS at 37 in a humidified incubator with 5% CO2.
  • MTT is a tetrazolium salt cleaved by mitochondrial dehydrogenases of living cells. Cleavage converts yellow, water soluble MTT to an insoluble, purple formazan crystal.
  • the crystals can be solubilized with a 50% ⁇ , ⁇ -dimethylformamide (vol/vol), 20% SDS
  • Veliparib 50 ⁇
  • Gemcitabine 0.6 ⁇ ) 1 .3 ⁇ 0.8 1 .4
  • mice NU-NU, Female, 5-6 weeks
  • Control group (0.9% NaCI (ip): 33 times; 4 times a week.
  • Pentamidine bis(2-hydroxyethanesulfonate) salt 45 mg/kg (ip)): 15 times:
  • Veliparib (Vel) 25 mg/kg (ip): 5 times:
  • Pentamidine bis(2-hydroxyethanesulfonate) salt 45 mg/kg (ip) + Veliparib (Vel) (25 mg/kg (ip)): pentamidine and Veliparib were provided same as pentamidine in 2 and Veliparib in 3 above.

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Abstract

La présente invention concerne une combinaison comprenant une quantité thérapeutiquement efficace (1) d'au moins un composé de diamidine et (2) d'au moins un inhibiteur de PARP pour inhiber la prolifération des cellules cancéreuses chez un patient en ayant besoin et/ou pour traiter le cancer chez un patient en ayant besoin, un procédé et les utilisations de ceux-ci.
PCT/CA2013/050509 2012-07-13 2013-06-28 Combinaisons comprenant des composés diamidine et des inhibiteurs de parp à utiliser dans le traitement du cancer WO2014008592A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2388674C (fr) * 1999-11-16 2005-01-25 Oncozyme Pharma Inc Inhibiteurs de l'activite des endo-exonucleases destines au traitement du cancer
CA2758856A1 (fr) * 2009-05-01 2010-11-04 Oncozyme Pharma Inc. Combinaisons de pentamidine pour traiter le cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2388674C (fr) * 1999-11-16 2005-01-25 Oncozyme Pharma Inc Inhibiteurs de l'activite des endo-exonucleases destines au traitement du cancer
CA2758856A1 (fr) * 2009-05-01 2010-11-04 Oncozyme Pharma Inc. Combinaisons de pentamidine pour traiter le cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MADHUSUDAN ET AL.: "The emerging role of DNA repair proteins as predictive, prognostic and therapeutic targets in cancer", CANCER TREATMENT REVIEWS, vol. 31, no. ISSUE., December 2005 (2005-12-01), pages 603 - 617 *

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