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WO2009056952A1 - Bisphosphonates géminaux, leur préparation et leur utilisation dans le domaine de l'oncologie - Google Patents

Bisphosphonates géminaux, leur préparation et leur utilisation dans le domaine de l'oncologie Download PDF

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WO2009056952A1
WO2009056952A1 PCT/IB2008/002904 IB2008002904W WO2009056952A1 WO 2009056952 A1 WO2009056952 A1 WO 2009056952A1 IB 2008002904 W IB2008002904 W IB 2008002904W WO 2009056952 A1 WO2009056952 A1 WO 2009056952A1
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ethylidene
chosen
imidazo
bisphosphonic acid
purin
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Nicola Gebbia
Daniele Simoni
Francesco Dieli
Manlio Tolomeo
Francesco Paolo Invidiata
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TETRAPHARM Srl
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    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • C07F9/65068—Five-membered rings having the nitrogen atoms in positions 1 and 3 condensed with carbocyclic rings or carbocyclic ring systems
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    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Definitions

  • the present invention relates to bisphosphonic geminal compounds (or geminal biphosphonates), having a structure comparable to that of zoledronic acid, a method for their preparation, their pharmaceutical formulations and their use in oncology, for the treatment of tumoral pathologies.
  • the present invention describes the use of said biphosphonates for the preparation of pharmaceutical compositions for the treatment of tumoral pathologies which are not associated with, nor could be associated with, nor are dependent on calcium.
  • Geminal bisphosphonates are compounds having analogue chemical structure to that of endogenous pyrophosphate in which a carbon atom replaces the central atom of oxygen. This carbon substitution makes these compounds resistant to hydrolysis (that is, more stable in an organism's interior) and allows the addition onto said carbon atom of two chains of variable structure, which can influence the pharmacologic activity thereof.
  • One of these side chains usually contains a hydroxyl moiety that allows high affinity for calcium crystals and bone mineral. The affinity to calcium conferred by said hydroxyl moiety is significantly added to that conferred by the presence of other free hydroxyl groups (acid) on the two phosphoric acid residues.
  • the here above geminal bisphosphonates are well-known, and as such also well used in therapy, for their ability to inhibit bone resorption. Consequently, the pharmacologic activity of said derivatives is, notoriously, strictly correlated and dependent on calcium and the mineral part of the bone.
  • these biphosphonates compounds chosen from the group comprising: zoledronic acid, ibadronic acid, etidronic acid and pamidronic acid.
  • biphosphonates Due to the strong calcium affinity as mentioned above, some of said biphosphonates have a certain anti-tumoral activity (for example anti-myeloma) in those specific pathologies which are associated with and/or could be associated with and/or are dependent on calcium.
  • anti-tumoral activity for example anti-myeloma
  • An object of the present invention is the use of said compounds for the preparation of a medicament (that is, a pharmaceutical composition) for the treatment of tumoral pathologies (and/or pathologies related thereto) which are not associated with and/or could not be associated with and/or are not dependent on calcium, as reported in the annexed independent claims.
  • an object of the present invention is the use of said compounds for the preparation of a pharmaceutical composition for the treatment of pathologies related or due to abnormal angiogenesis, as reported in the annexed claims.
  • Another object of the present invention are the geminal biphosphonate compounds having the ability mentioned here above and their pharmaceutical formulations, as reported in the annexed claims. Preferred embodiments of the present invention are further detailed in the annexed dependent claims.
  • Figure 1 shows graphically the inhibitory effect, exercised at different dosages, of one of the preferred compounds of the present invention (indicated as MM32 and described in Example 2) on the growth of different tumour cell lines
  • Figure 2 shows graphically the inhibitory effect of Zoledronic acid (at the corresponding dosages of MM32 shown in Figure 1) on the growth of the same cellular lines shown in Figure 1 (HUT78; K562; CEM; and CEM VBL300 respectively).
  • Figure 3 shows, in a histogram, the percentage of apoptosis induced by MM32 at 100 ⁇ M concentration compared to the percentage of apoptosis induced by Zoledronic acid, on cellular lines HUT78, K562, CEM and CEM VBL 300 respectively.
  • Figure 4 shows in a histogram the percentage of apoptosis induced by the combination of imatinib+zoledronic acid and, respectively, the combination of imatinib+MM32 compared to that of irnatinib alone on the cellular line K562; the compound imatinib being at 0.25 ⁇ M concentration while both zoledronic acid and MM32 are at 30 ⁇ M concentration.
  • Figure 5 shows, in a histogram, the low toxicity of MM32 compared to that of zoledronic acid on normal hemopoietic stem cells (CFU-CM cell line); the cytotoxic effect was determined using concentrations of MM32 and Zoledronic acid that varied from 20 to 100 ⁇ M .
  • - Ri is chosen from: H, CH 3 , C 2 H 5 , CH 2 -C 6 H 5 , C 3 H 75 C 6 H 5 ;
  • - Y is chosen from: H, halogen, NH 2 ;
  • - X is chosen from: CH 2 , CH 2 NH 5 CH 2 O;
  • R 2 is a heterocyclic residue chosen from: imidazole, benzoimidazole, benzopyrrole, indole, indazole, pyrazole, pyridine, pyridazine, pyrazine, pyrolidine, pyperazine, pyperidine, imidazopyridazine, imidazopyrazyne, imidazopyridine, purine: said residues being possibly substituted with at least one moiety chosen from: CH 3 , C 6 H 5 , OCH 3 , NH 25 NO 2 , CN 5 COOH 5 halogen,
  • R 5 is alkyl Ci - C 4 or acyl C 1 - C 4 ; their enantiomers, diastereoisomers, the respective mixtures and/or their pharmaceutically acceptable salts, for use in the treatment of a pathology through the activation of ⁇ T-lymphocytes.
  • said pathology is a tumoral pathology that is not associated with and/or could not be associated with and/or is not dependent on calcium.
  • the present invention relates to the compounds of formula (I) and pharmaceutical compositions that comprise at least one of said compounds.
  • R 1 groups in formula (I) described here above represent moieties that can be the same or different between themselves.
  • the halogen is chlorine.
  • said compounds of formula (I) are chosen from the group in which:
  • R 1 is chosen from: H, CH 3 , C 2 H 5 , CH 2 -C 6 H 5 , C 3 H 7 and C 6 H 5,
  • R 2 is chosen from:
  • said compounds of formula (I) are chosen from the group in which:
  • R 1 is chosen from H, CH 3 , C 2 H 5 ;
  • - Y is H; - X is CH 2 ;
  • - R 2 is chosen from:
  • the formula (I) compounds are structural analogues of zoledronic acid, in which the OH group on the central carbon atom of the molecule is eliminated so as to diminish the affinity of the compound for calcium.
  • the imidazole residue of the zoledronic acid is variably substituted with aromatic and non-aromatic heterocyclic residues.
  • residues are preferably chosen from the group comprising: imidazole, benzoimidazole, benzopyrrole, indole and indazole, pyrazole, pyridine, pyridazine, pyrazine, pyrrolidine, pyperazine, pyperidine, imidazopyridazine, imidazopyrazyne, imidazopyridine, purine.
  • Formula (I) compounds unexpectedly show a strong efficacy in activating ⁇ T- lymphocytes.
  • said compounds show an activation which is on average 100 fold higher, up to 1000 fold higher and even more.
  • said compounds have also shown to have a high cytotoxic and high apoptotic activity, therefore being highly suitable as anticancer agents.
  • formula (I) compounds have shown to be particularly useful in the treatment of tumoral pathologies that are tumoral pathologies which are not associated with and/or could not be associated and/or are not dependent on calcium.
  • said compounds are shown to be useful in the treatment of at least a tumoral pathology sensitive to the effect of substances that activate ⁇ T-lymphocytes.
  • said compounds have shown to be useful in the treatment of at least a tumoral pathology sensitive to the effect of substances having cytotoxic activity.
  • said compounds have shown to be useful in the treatment ' of at least a tumoral pathology sensitive to the effect of substances having an apoptotic activity.
  • one or more formula (I) compounds according to the present invention are useful for the preparation of a pharmaceutical composition for the treatment of at least one tumoral pathology which is not associated with and/or could not be associated with and/or is not dependent on calcium; wherein said tumoral pathology is chosen from the group comprising: , sarcoma, carcinoma, carcinoid tumor, renal carcinoma, colon cancer, breast cancer, bones cancer, neuroendocrine cancer, prostate cancer, leukaemia, chronic myelogen leukaemia, positive Bcr-Abl leukaemia, lymphoid leukaemia, myeolid leukaemia, megakariocytic leukaemia, non-Hodgkin lymphoma, melanoa, Hodgkin disease, tumoral pathologies sensitive to immunotherapy, gastrointestinal stromal cancer (G)
  • Formula (I) compounds have also shown an activity also toward pathologies that are related to tumoral disease described above, for example abnormal angiogenesis. Consequently, an additional object of the present invention is the use of said compounds for the preparation of a pharmaceutical composition for the treatment of pathologies associated with and/or which could be associated with abnormal angiogenesis.
  • said pathologies associated with and/or which could be associated with abnormal angiogenesis are chosen from a group . comprising: arthritis, tumor sensitive to angiogenic activity, metastatic diffusion, diabetic retinopathy, psoriasis, chronic inflammation, atherosclerosis.
  • said one or more compound of formula (I) are formulated in combination with at least one compound having antiblastic activity.
  • Said at least one compound having antiblastic activity is preferably chosen from the group comprising: alkylating agents, topoisomerase inhibitors, inhibitors of the mitotic spindle, intercalating agents, antimetabolites, products of natural origin such as Vinca alkaloids, epidophyllotoxins, antibiotics, enzymes, taxanes, anticancer vaccine.
  • the Reaction scheme 1 is a synthesis reaction that illustrates the preparation of formula 1 compounds, with specific reference to preferred compounds. The same conditions are however easily applicable by the person skilled in the art, for the preparation of the other compounds of formula (I).
  • Said Reaction Scheme I summarises the method used for the preparation of different classes of bisphosphonate of Formula (I), wherein the corresponding germinal bisphosphonate (that is the biphosphonic esters) were prepared from the corresponding methylene-bisphosphonates by treatment with the appropriate NH-derivative, as shown in said reaction scheme, and with TBD (that is, 1,5,7- triazyabicyclo[4.4.0]dec-5-ene) acting as catalyst in the presence, or not, of an appropriate solvent.
  • TBD that is, 1,5,7- triazyabicyclo[4.4.0]dec-5-ene
  • the geminal bisphosphonates according to the invention will be prepared from the corresponding methylenebisphosphonate by treatment with the appropriate NH-derivative at 140-170°C for 10-20 minutes in a microwave emitting oven.
  • the corresponding bisphosphonic acid were in turn obtained starting from the corresponding ester derivatives by treatment with acid.
  • Method B a mixture of a compound a-1 (1.1 equiv) and compound 1 (1 equiv.) in THF was stirred under reflux for 4h, after which the solvent was evaporated in vacuo.
  • the crude resultant material was dissolved in water and extracted with dichloromethane; the organic phases were collected, dried under anhydrous sodium sulphate, filtered and evaporated.
  • the crude material was purified by flash chromatography on silica gel with dichloromethane-methanol as eluant (98:2/v:v). Yield: 40-70%.
  • Method A a solution of one of compounds 2a-l is stirred under reflux for 3h in concentrated HCl, and the solvent evaporated in vacuo. The residual solid is recrystallized from H 2 O-MeOH to give correspondent compound 3a-l in the form of white or yellow solids.
  • Method B to a solution, cooled in an ice-bath, of one of the compounds 2a-l (1 equiv.) in CCl 4, 4,2 equiv. of iodotrimethylsilane was added dropwise, and the resulting mixture was stirred for 3h at a temperature below 5 "C.
  • the reaction . mixture was quenched by adding methanol and the precipitate thus formed was collected and recrystallized by from H 2 O-MeOH to give correspondent compound 3a-l as white or yellow solid.
  • the active ingredient or the mixture thereof is normally present in a quantity able to produce a significative therapeutic effect.
  • Said quantity as also the posology in administering, will be determined by the type of pathology which needs to be confronted.
  • the dosage could be analogous to those currently used for 'biphosphonates presently used in therapy of the skeletal system.
  • said dosage could vary, even substantially, with respect to a series of factors, such as, for example, age and state of the patient, type of pathology and its gravity, toxicity of the active ingredient or the mixture thereof, posology required and so on.
  • compositions covered by the present invention are entirely conventional and are obtained using methods which are common practice in the pharmaceutical industry, such as are illustrated, for example, in Remington's Pharmaceutical Science Handbook, Mack Pub. N. Y. 2005). According to the chosen administration route, the compositions will be in solid or liquid form, suitable for oral, parental or intravenous administration.
  • said pharmaceutical composition comprises also at least one pharmaceutically acceptable vehiculanting agent and/or one excipient and/or pharmaceutically acceptable diluent, such as, for example, ssolubilising agents, dispersing agents, suspension agents and emulsifying agents.
  • Example 1 - Activation of human ⁇ T-lymphocytes by biphosphonates according to formula 3 a-c, g Biphosphonates 3a-c, g were extremely efficient in inducing activation in vitro of human V ⁇ 9V ⁇ 2 T-lymphocytes after in vitro culturing of peripheral blood mononuclear cells (PBMC) in the presence of low dose (20 U/ml final concentration) of interleukin (IL)-2.
  • PBMC peripheral blood mononuclear cells
  • IL interleukin
  • biphosphonates have produced a differentiation of the phenotype of the natural immature cells and memory cells to effector cells which expediate important functions (such as production of TNF-alpha and IFN-gamma and cytotoxicity) against tumoral cell lines in vitro.
  • biphosphonates when compared with zoledronic acid, have been shown to activate and differentiate V ⁇ 9V ⁇ 2 T-lymphocytes more than 100 times more, even though they share a similar structure.
  • Example 2 Synergic effects of formula CI) compounds and imatinib mesilate (Gleevec)
  • the cytotoxic activity of these compounds on normal cells from the hematopoietic marrow was also evaluated.
  • the compound 3 a (hereafter MM32) is shown as an example: the derivatives 3b,c,g,j have shown to have a similar activity.
  • Zoledronic acid is used as a reference compound according to the prior art.
  • the cytotoxic activity of zoledronic acid and of the derivative MM32 is tested on the following human cell lines: HUT78 (T cell lymphoma); HUT78B 1 (T cell lymphoma resistant to Fas ligand);
  • K562 acute myeloid leukaemia expressing anti-apoptotic oncogene Bcr-Abl
  • CCRF-CEM acute lymphoblastic leukaemia
  • CCRF-CEM VBL300 acute lymphoblastic leukaemia expressing P- glycoprotein
  • 2x10 5 cells were exposed to zoledronic acid and to MM32 at concentrations ranging from 10 to 200 ⁇ M. After 48 h, the cells were harvested and counted by a cell counter after staining with trypan blue. The number of living cells in treated samples was compared with the number of cells counted in control samples (no treated samples) and expressed as percentage of living cells respect to the control. The percentage of apoptotic cells induced by zoledronic acid and MM32 was calculated by using the following methods:
  • MM32 compound shows an antiproliferative effect higher than that of zoledronic acid in HUT78 cells ( Figures 1, 2).
  • Zoledronic acid used at a concentration of lOO ⁇ M caused the induction of apoptosis in 25% of HUT78 cells, while MM32 (100 ⁇ M) induced 40% (Fig. 3).
  • the expression of the P-glycoprotein on the cell surface membrane (multi-drug resistance-MDR) is one of the most important cause of resistance toward chemotherapy.
  • the effects of MM32 on MDR expressing leukaemia cell line CCRF-CEM VBL 300 were studied and the results obtained were compared with those observed in the parental sensitive cell line CCRF-CEM.
  • MM32 was not particularly active in CCRF-CEM cells. However, the MM32 compound, but not zoledronic acid, was unexpectedly more active in the MDR cells than in the parental CCRP-CEM cell line (Fig. 1, 2 and
  • Both zoledronic acid and MM32 were not active on Bcr-Abl expressing K562 cells when used at concentrations lower than 50 ⁇ M (Fig 1, 2 e 3).
  • the effects of the combination of imanitib with MM32 compared to the combination of zoledronic acid and imanitib were evaluated.
  • K562 cells were exposed to different concentrations of imatinib in association with zoledronic acid or MM32 at a concentration of 30 ⁇ M, which is a concentration which is not cytotoxic for K562 cells. It was seen that 25 ⁇ M imatinib caused a cell growth inhibition of 50%; however this concentration was not able to induce apoptosis.
  • renal and myeloma tumour represent two important forms of tumour in which pharmaceuticals able to activate ⁇ T-lymphocytes, like the compounds of formula (I), prove to be particularly useful
  • These compounds are particularly promising in the treatment of colon carcinoma, V ⁇ 9V ⁇ 2 T-lymphocytes clones having been recently shown to be exercising a cytotoxic activity on colon carcinoma cells and not normal colon cells.
  • the compounds of formula (I) are particularly promising even for the treatment of mammary carcinoma, of prostate carcinoma and non-Hodgkin lymphoma. In these cases, it is also foreseen that it is preferable to use an association of at least one of two compounds of formula
  • Example 3 In vivo demonstration of the antitumor activity of human ⁇ T- lymphocytes
  • SCID mice (6 mice per group) were conditioned by irradiation (300 rads from a caesium source) and anti-asialo-GMl monoclonal antibody (BD Bioscience) treatment.
  • mice received a single intraperitoneal injection of 2 x 10 6 BT549 cells. These high numbers of tumour cells were inoculated to allow for full-fledged tumour growth within the period before graft-vs.-host reactions developed in the SCID mouse reconstituted with human lymphocytes.
  • mice received concomitantly with the tumour cells an intraperitoneal injection of: a) human recombinant (r)IL-2 (300 ng), or b) MM32 (2 ⁇ g), or c) zoledronate (5 ⁇ g), or d) MM32 (2 ⁇ g) plus rIL-2 (300 ng), or e) zoledronate (5 ⁇ g) plus rIL (300 ng).
  • mice received, in addition, highly purified 2 x 10 7 human ⁇ T-lymphocytes (which had been previously expanded in vitro from peripheral blood mononuclear cells of healthy volunteers).
  • the scheme of treatment used for the different groups 1-9 is indicated in Table 1, while in Table 2 the median survival rates of the groups 1-9 of mice is indicated.

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Abstract

La présente invention concerne des composés bisphosphoniques géminaux, pouvant être structurellement associés à l'acide zolédronique, un procédé pour leur préparation, leur composition pharmaceutique et leur utilisation en oncologie pour le traitement de pathologies tumorales.
PCT/IB2008/002904 2007-10-30 2008-10-30 Bisphosphonates géminaux, leur préparation et leur utilisation dans le domaine de l'oncologie Ceased WO2009056952A1 (fr)

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IT000034A ITPA20070034A1 (it) 2007-10-30 2007-10-30 Bifosfonati geminali, loro preparazione e loro impiego in campo oncologico.

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US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
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US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
CN109369721A (zh) * 2017-12-21 2019-02-22 深圳市塔吉瑞生物医药有限公司 用于抑制激酶活性的芳基磷氧化物

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10323052B2 (en) 2009-07-31 2019-06-18 Grunenthal Gmbh Crystallization method and bioavailability
US8933057B2 (en) 2009-07-31 2015-01-13 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9169279B2 (en) 2009-07-31 2015-10-27 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US9334296B2 (en) 2009-07-31 2016-05-10 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US8399023B2 (en) 2009-07-31 2013-03-19 Thar Pharmaceuticals, Inc. Crystallization method and bioavailability
US10093691B2 (en) 2009-07-31 2018-10-09 Grunenthal Gmbh Crystallization method and bioavailability
US9340565B2 (en) 2010-11-24 2016-05-17 Thar Pharmaceuticals, Inc. Crystalline forms
US10519176B2 (en) 2010-11-24 2019-12-31 Thar Pharma, Llc Crystalline forms
WO2016081281A1 (fr) * 2014-11-17 2016-05-26 Salk Institute For Biological Studies Bisphosphonates lipophiles et procédés d'utilisation
WO2016098904A1 (fr) * 2014-12-19 2016-06-23 国立大学法人 長崎大学 Nouveau dérivé d'acide bisphosphonique et application associée
US10532065B2 (en) 2014-12-19 2020-01-14 Nagasaki University Bisphosphonic acid derivative and application for same
US10195218B2 (en) 2016-05-31 2019-02-05 Grunenthal Gmbh Crystallization method and bioavailability
CN109369721A (zh) * 2017-12-21 2019-02-22 深圳市塔吉瑞生物医药有限公司 用于抑制激酶活性的芳基磷氧化物
CN109369721B (zh) * 2017-12-21 2024-05-14 深圳市塔吉瑞生物医药有限公司 用于抑制激酶活性的芳基磷氧化物

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