AU2011204918B2

AU2011204918B2 - Use of alkylphosphocholines in combination with antitumor medicaments

Info

Publication number: AU2011204918B2
Application number: AU2011204918A
Authority: AU
Inventors: Jurgen Engel; Eckhard Gunther; Herbert Sindermann
Original assignee: Aeterna Zentaris GmbH
Current assignee: Aeterna Zentaris GmbH
Priority date: 2002-07-30
Filing date: 2011-07-21
Publication date: 2012-04-12
Anticipated expiration: 2023-07-29
Also published as: AU2011204918A1

Abstract

USE OF ALKYL PHOSPHOCHOLINES IN COMBINATION WITH ANTITUMOR MEDICAMENTS 5 Abstract The invention relates to the use of alkyl phosphocholines in combination with antitumor medicaments for treating benign and malignant tumor diseases in humans and mammals. The alkyl phosphocholines can be used in an inventive combination with one or a combination of several approved cytostatics. Preferred alkyl phosphocholines are io represented in formula II: o (CH2)z R-(CH -O-(CH 2)p N 0- (CH 2 )n formula II.

Description

S&F Ref: 705728D2 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address /Eterna Zentaris GmbH, of Weismullerstrasse 50, D of Applicant : 60314, Frankfurt, Germany Actual Inventor(s): Eckhard Gunther Jurgen Engel Herbert Sindermann Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Use of alkylphosphocholines in combination with antitumor medicaments The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(5464474_1) Use of alkylphosphocholines in combination with antitumor medicaments Alkylphosphocholines are a new class of organic compounds which show diverse antineoplastic activities (M. Lohmeyer and R. Bittman; Antitumor ether lipids and alkylphosphocholines, DOF, 19 (11), 1021-1037 (1994)). The effect of the 5 alkylphosphocholines in this connection may be based on various molecular and biochemical mechanisms, some of which take place at the level of the plasma membrane of the cells. It is well known that alkylphosphocholines influence inositol metabolism, the interaction with phospholipases or inhibition of protein kinase C and thus that this class of substances has a general influence on cellular signal 10 transduction (K. Maly, F. Overall, C. Schubert, E. Kindler, J. Stekar, H. Brachwitz and H. H. Grunicke, Interference of new alkylphospholipid analogues with mitogenic signal transduction, Anti-Cancer Drug Design, 10, 411-425 (1995)). Thus, the alkylphosphocholine perifosine shows growth-inhibitory properties in relation to various melanoma, CNS, lung, colon, prostate and breast cancer cell lines with an 5 ICso in the region of 0.2 - 20 pM (P. Hilgard, T. Klenner, J. Stekar, G. N6ssner, B. Kutscher and J. Engel; D-21266, a New Heterocyclic Alkylphospholipid with Antitumor Activity, Eur. J. Cancer, 33 (3), 442-446 (1997)). It is further known that perifosine blocks tumor cells in the G-S and G 2 -M phase of the cell cycle (V. Patel, T. Lahusen, T. Sy, E. A. Sausville, J. S. Gutkind and A. M. Senderowicz; Perifosine, 20 a Novel Alkylphospholipid, Induces p21Waf' Expression in Squamous Carcinoma Cells through a p53-independent Pathway, Leading to Loss in Cyclin-dependent Kinase Activity and Cell Cycle Arrest, Cancer Research 62, 1401-1409 (2002)). It is known that the use of alkylphosphocholines before or together with radiotherapy leads to synergistic effects in the treatment of tumors (G.A. Ruitter, M. Verheijl, 25 S.F. Zerp and W.J. van Blitterswijk; Alkyl-Lysophospholipids as Anticancer Agents and Enhancers of Radiation-Induced Apoptosis, Int. J. Radiation Oncology Biol. Phys., 49 (2), 415-420, 2001). It has also been reported that various glycero-3 phospholipids, e.g. ET-18-OCH 3 , in combination with various DNA-interacting substances or tubulin binders increase the antitumor activity in vitro on various tumor 30 cell lines (A. Noseda, M.E. Berens, J.G. White and E.J. Modest; In vitro antiproliferative activity of combinations of ether lipid analogs and DNA-Interactive 2 agents against human tumor cells, Cancer Res., 48 (7), 1788-1791 (1988); P. Principe, H. Coulomb, C. Broquet and P. Braquet; Evaluation of combinations of antineoplastic ether phospholipids and chemotherapeutic drugs, Ant-Cancer Drugs, 3 (6), 577-587 (1992); P. Principe, H. Coulomb, J.-M. Mencia-Huerta, C. Broquet and 5 P. Braquet; Synergistic cytotoxic effect of aza-alkylphospholipids in association with chemotherapeutic drugs, J. Lipid Mediators Cell Signalling, 10 (1-2), 171-173 (1994)). It has now been possible, surprisingly, to show that linear alkylphosphocholines of the general formula I and I are suitable for use in a combination according to the 10 invention with other drug products for the treatment of benign and malignant oncoses in humans and mammals. It is possible in this connection for the compounds of the general formula I and 11 to be employed in a combination according to the invention with antitumor substances. Antitumor substances may be alkylating agents, antimetabolites, plant alkaloids, platinum compounds, tumor antibiotics and agonists 16 or antagonists of natural hormones. The antitumor substances may be selected from but not restricted to: cisplatin, carboplatin, oxaliplatin, bleomycin, doxorubicin, methotrexate, paclitaxel, docetaxel, vincristine, vinblastine, etoposide, teniposide, ifosfamide, cyclophosphamide, 5-fluorouracil, fludarabine, gemcitabine and cytarabine. 20 It is moreover possible for the alkylphosphocholines of the general formula I and I to be employed in a claimed combination with inhibitors of signal transduction in the form of high and low molecular weight inhibitors of receptor and/or cytosolic kinases. These inhibitors may be selected from but not restricted to monoclonal antibodies and heterocyclic compounds. 25 The alkylphosphocholines of the general formula I and Il pn which the invention is based can be used in the form of finished drug products. The compounds on which the invention is based are described by the general formulae I and II: 3 O R3" ./RI

R-(CH

2 )m (CH 2 )n o formula I X'I H +

P--(H

2 )p-C N Fa o

(CH

2 )n formula I 5 where, independently of one another: n, m, p, z are an integer between 0 and 4; X is O, S, NH; R is H, a straight-chain or branched (C-C 20 )-alkyl radical which may be saturated or unsaturated with one to three double and/or triple bonds and 0 which may be unsubstituted or optionally substituted on the same or on different C atoms by one, two or more halogen, nitro, cyano, hydroxyl,

(C-C

6 )-alkoxy, amino, mono-(C-C 4 )-alkylamino or di-(C-C 4 )-alkylamino radicals.

R

1 , R 2 , R 3 is, independently of one another, H, a straight-chain or branched (C-C 6

)

I5 alkyl radical, preferably methyl and ethyl, a (C 3

-C

7 )-cycloalkyl radical and which may be unsubstituted or optionally substituted on the same or on different C atoms by one, two or more halogen, nitro, cyano, hydroxyl,

(C-C

6 )-alkoxy, amino, mono-(C-C 4 )-alkylamino or di-(C-C 4 )-alkylamino radicals.

- 3a Accordingly, a first aspect of the present invention provides the use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of benign and malignant oncoses before and/or during treatment with an antimetabolite selected from the group consisting of 5-azacytidine, clofarabine, gemcitabine, 5 5 fluorouracil and capecitabine or a combination thereof. A second aspect of the present invention provides the use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of metastatic colon cancer before and/or during treatment with the antimetabolite 5 fluorouracil. 10 A third aspect of the present invention provides the use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of metastatic colorectal cancer before and/or during treatment with the antimetabolite 5 fluorouracil in combination with capecitabine. A fourth aspect of the present invention provides the use of the is alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of multiple myeloma before and/or during treatment with the antimetabolites 5 azacytidine, clofarabine and gemcitabine. A fifth aspect of the present invention provides the use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of multiple myeloma 20 before and/or during treatment with the antimetabolite 5-azacytidine. There is also disclosed a method for controlling tumors in humans and in mammals which comprises administering at least one of the compounds of the general formula I and II on which the invention is based to the human or a mammal in an amount effective for tumor treatment before or during a treatment with approved 25 antitumor substances. Specifically a sixth aspect of the present invention provides a method for the treatment of benign or malignant oncoses in a mammal, the method comprising administering to said mammal an effective amount of the alkylphosphocholine perifosine before and/or during treatment with an antimetabolite selected from the group 30 consisting of 5-azacytidine, clofarabine, gemcitabine, 5-fluorouracil and capecitabine or a combination thereof. A seventh aspect of the present invention provides a method for the treatment of metastatic colon cancer in a mammal, the method comprising administering to said - 3b mammal an effective amount of the alkylphosphocholine perifosine before and/or during treatment with the antimetabolite 5-fluorouracil. An eighth aspect of the present invention provides a method for the treatment of metastatic colon cancer in a mammal, the method comprising administering to said 5 mammal an effective amount of the alkylphosphocholine perifosine before and/or during treatment with the antimetabolite 5-fluorouracil in combination with capecitabine. A ninth aspect of the present invention provides a method for the treatment of multiple myeloma in a mammal, the method comprising administering to said mammal io an effective amount of the alkylphosphocholine perifosine before and/or during treatment with the antimetabolites 5- azacytidine, clofarabine and gemcitabine. A tenth aspect of the present invention provides a method for the treatment of multiple myeloma in a mammal, the method comprising administering to said mammal an effective amount of the alkylphosphocholine perifosine before and/or during is treatment with the antimetabolite 5-azacytidine.

4 The therapeutically effective dose, to be administered for the treatment, of the particular compound of the general formula I and 11 on which the invention is based 5 depends inter alia on the nature and the stage of the oncosis, the age and sex of the patient, the mode of administration and the duration of treatment. The compounds on which the invention are based can be administered in a drug product as liquid, semisolid and solid drug forms. This takes place in the manner suitable in each case in the form of aerosols, oral powders, dusting powders and 10 epipastics, uncoated tablets, coated tablets, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, pastilles, capsules or suppositories. Exemplary embodiments: 1. Administration of perifosine (D-21 266) in combination with cisplatin In vivo test: DMBA-induced rat mammary carcinoma model S5 Experimental animal: Sprague-Dawley rat, female Procedure: The mammary carcinoma was induced by a single oral dose of DMBA. The animals received perifosine from day 0 to day 14 and were observed up to day 42. The weight of the tumor mass was estimated by palpation and comparison with plastic models. The 2:0 initial weight is set equal to 100%. Administration: Perifosine 14 x 6.81 mg/kg p.o. Cisplatin 4 x 1 mg/kg i.p. Effect: Reduction in the tumor was distinctly greater and longer through the combination treatment than through the single treatment in 25 each case.

5 Treatment Tumor Day 21 p test vs. Initial weight [g] Change in [%} Control Control 1.0 875 Perifosine (D-21266) 0.9 -25 <0.001 5 Cisplatin 0.9 410 0.120 Perifosine (D-21266) 0.8 -75 <0.001 + Cisplatin 2. Administration of perifosine in combination with cyclophosphamide In vivo test: DMBA-induced rat mammary carcinoma model 0 Experimental animal: Sprague-Dawley rat, female Procedure: The mammary carcinoma was induced by a single oral dose of DMBA. The animals received perifosine from day 0 to day 14 and were observed up to day 42. The weight of the tumor mass was estimated by palpation and comparison with plastic models. The 15 initial weight is set equal to 100%. Administration: Perifosine 14 x 6.81 mg/kg p.o. Cyclophosphamide 100 mg/kg, VZ 0, i.v. Effect: Reduction in the tumor was distinctly greater and longer through the combination treatment than through the single treatment in 20 each case.

6 Treatment Tumor Day 21 p test vs. Initial weight {g] Change in {%) Control Control 1.0 875 Perifosine (D-21266) 0.9 -25 <0.001 5 Cyclophosphamide 0.9 500 0.011 Perifosine (D-21266) 0.8 -83.3 <0.001 + Cyclophosphamide 3. Administration of perifosine in combination with Adriamycin In vivo test: DMBA-induced rat mammary carcinoma model 10 Experimental animal: Sprague-Dawley rat, female Procedure: The mammary carcinoma was induced by a single oral dose of DMBA. The animals received perifosine from day 0 to day 14 and were observed up to day 42. The weight of the tumor was mass was estimated by palpation and comparison with plastic models. 15 The initial weight is set equal to 100%. Administration: Perifosine 14 x 6.81 mg/kg p.o. Adriamycin 4 x 2.15 mg/kg i.p. Effect: Reduction in the tumor was distinctly greater and longer through the combination treatment than through the single treatment in zo each case.

Treatment Tumor Tag 21 p test vs. Initial weight [g] Change in [%] Control Control 1.0 875 Perifosine 0.9 -25 <0.001 5 (D-21266) Adriamycin 1.0 781.3 0.197 Perifosine 01.0 -70 <0.001 (D-21266) + Adriamycin

Claims

1. Use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of benign and malignant oncoses before and/or during treatment with an antimetabolite selected from the group consisting of 5-azacytidine, clofarabine, s gemcitabine, 5-fluorouracil and capecitabine or a combination thereof.

2. The use according to claim I wherein the perifosine is in a therapeutic dose that is effective for said treatment of benign and malignant oncoses before and/or during treatment with the antimetabolite.

3. The use according to claim I or claim 2 wherein the medicament comprises 10 customary pharmaceutical carriers, excipients and/or diluents.

4. The use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of metastatic colon cancer before and/or during treatment with the antimetabolite 5-fluorouracil.

5. The use of the alkylphosphocholine perifosine for the manufacture of a drug 15 product for the treatment of metastatic colorectal cancer before and/or during treatment with the antimetabolite 5-fluorouracil in combination with capecitabine.

6. The use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of multiple myeloma before and/or during treatment with the antimetabolites 5-azacytidine, clofarabine and gemcitabine. 20

7. The use of the alkylphosphocholine perifosine for the manufacture of a drug product for the treatment of multiple myeloma before and/or during treatment with the antimetabolite 5-azacytidine.

8. A method for the treatment of benign or malignant oncoses in a mammal, the method comprising administering to said mammal an effective amount of the 25 alkylphosphocholine perifosine before and/or during treatment with an antimetabolite selected from the group consisting of 5-azacytidine, clofarabine, gemcitabine, 5 fluorouracil and capecitabine or a combination thereof.

9. The method according to claim 8 wherein the perifosine is in a therapeutic dose that is effective for said treatment of benign and malignant oncoses before and/or 30 during treatment with the antimetabolite.

10. The method according to claim 8 or claim 9 wherein the medicament comprises customary pharmaceutical carriers, excipients and/or diluents.

11. A method for the treatment of metastatic colon cancer in a mammal, the method comprising administering to said mammal an effective amount of the -9 alkylphosphocholine perifosine before and/or during treatment with the antimetabolite 5 fluorouracil.

12. A method for the treatment of metastatic colon cancer in a mammal, the method comprising administering to said mammal an effective amount of the 5 alkylphosphocholine perifosine before and/or during treatment with the antimetabolite 5 fluorouracil in combination with capecitabine.

13. A method for the treatment of multiple myeloma in a mammal, the method comprising administering to said mammal an effective amount of the alkylphosphocholine perifosine before and/or during treatment with the antimetabolites 5 io azacytidine, clofarabine and gemcitabine.

14. A method for the treatment of multiple myeloma in a mammal, the method comprising administering to said mammal an effective amount of the alkylphosphocholine perifosine before and/or during treatment with the antimetabolite 5 azacytidine.

15 Dated 19 March, 2012 Eterna Zentaris GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON