Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

• Combined therapy comprising nemorubicin and a Cyclooxygenase-2 inhibitor
• the present invention pertains to the field of neoplastic diseases therapy.
• this invention relates to a method for treating cancer in a subject in need of such a treatment, said method
• compositions or packaged units comprising a morpholinyl anthracycline derivative and is a Cox-2 inhibitor.
• Cancers are a leading cause of death in humans and animals; surgery, radiation and chemotherapy are the useful means to fight
• 25 select antitumor combinations more and more active and safe to be administered to a patient suffering from a cancer.
• the present invention fulfills such a need by providing a mo ⁇ holinyl anthracycline derivative a pharmaceutically acceptable salt or a metabolite thereof administered in combination with a Cox-2 inhibitor.
• a mo ⁇ holinyl anthracycline derivative a pharmaceutically acceptable salt or a metabolite thereof administered in combination with a Cox-2 inhibitor.
• compositions and kits to effect these methods.
• a preferred morpholinyl anthracycline derivative is the morpholinyl anthracycline derivative of
• the term "metabolite” embraces all derivatives resulted from an enzymatic biotransformation of a mo ⁇ holinyl anthracycline derivative according to the invention.
• the chemical reactions of enzymatic biotransformation are classified as ⁇ hase-1 or 5 phase-ll reactions.
• salts refers to those salts, which retains the biological effectiveness and properties of the parent compound.
• Such salts include acid addition salt which is
• nemombicin includes, unless otherwise specified, the mo ⁇ holinyl anthracycline derivative of formula (I) and its pharmaceutically acceptable salts, especially the hydrochloride salt.
• nemorubicin is significantly more potent In vivo than in vitro. This observation suggested an in vivo metabolism of the drug to potent metabolite/s. In in vitro experiments, in the presence of mouse,
• nemorubicin is metabolized to potent metabolite/s. Microsomal activation appears to occur also in vivo since nemorubicin is highly effective on liver metastases. Nemorubicin is currently undergoing clinical evaluation; clinical data obtained so far suggest an interesting affinity of nemorubicin for liver lesions, even in tumor types resistant to conventional chemotherapy.
• Examples of identified metabolites of nemorubicin are compounds of the below formulae (III) to (VI)
• the metabolites of the above formulae (III), (IV) (V) and (VI) are active antitumor compounds "per se”. 5
• the preparation of the compound of formula (III) may be carried out, for example, following the procedure disclosed in GB 2325067.
• the preparation of the compound of formula (IV) may be carried out, for example, following the procedure disclosed in GB 2247885.
• the preparation of the compounds of formula (V) and (VI) may be 10 carried out, for example, following the procedure disclosed in GB
• the compounds of formulae (II) to (VI) may also exist In the form of a pharmaceutically acceptable salt, in this case preferred salts are hydrochloride salts.
• preferred salts are hydrochloride salts.
• the present invention embraces a combined preparation comprising a compound of the above formula (III), (IV) (V) or (VI) administered In combination with a Cox-2 inhibitor.
• MX2 a mo ⁇ holinyl anthracycline belonging to the family of 3'- 20 deamine-3'(4-mo ⁇ holinyl) derivatives of 10-hydroxy-13- deoxocarminomycln, was described and claimed in Otake et al., US patent no.4,710,564.
• MX2 is active in vitro and in vivo on tumor cells resistant to anthracyclines and presenting the multi-drug resistant phenotype. 25 No cross-resistance was observed on tumor cells resistant to CTX, L-
• MX2 is active in vivo after i.p., i.v. and oral administration, with good antileukemic and antitumor activity on muri ⁇ e and human tumor models.
• X2 is highly lipophilic and less cardiotoxic than DX.
• the 30 major dose limiting factor of MX2 is myelosuppression.
• cyclooxygenase-2 (Cox-2) is an immediate-early response gene. Extensive studies have recognized its overexpresslon in several carcinomas and Its implication in carcinogenesis and tumor progression. Recent clinical studies have Indicated that the presence of Cox-2 in human lung and colon is associated with poor prognosis and that overexpresslon of Cox-2 might be one of the leading factors in hepatic carcinogenesis (Clin. Cancer Res. 5:1001-5, 1999; Clin. Cancer Res.6:4064-6, 2000; Clin. Cancer Res. 7:1325-32, 2001).
• cyclooxygenase-2 inhibitor as used herein, embraces compounds, which selectively inhibi t Cox-2 over cyclooxygenase-1, and also includes pharmaceutically acceptable salts of those compounds.
• Cox-2 selective inhibitors to be used in combination with a mo ⁇ holinyl anthracycline derivative according to the invention are chromene Cox-2 selective inhibitors listed in Table 1.
• the compound SD-8381 shown as the structure in figure B-8 above, is a preferred chromene-type Cox-2 selective inhibitor to be used in combination with a mo ⁇ holinyl anthracycline derivative according to the present invention.
• the sodium salt form of the compound is preferred. Further information about SD-8381 can be found in U.S. Patent No. 6,034,256.
• cyclooxygenase-2 inhibitor to be used in combination with a mo ⁇ holinyl anthracycline derivative of the present invention can be selected from the class of tricyclic Cox-2 selective inhibitors listed in Table 2.
• the Cox-2 selective inhibitor to be combined with a morpholinyl anthracycline derivative of the present invention can be selected from the group of compounds, illustrated in Table 2. consisting of celecoxib (B-18), valdecoxib (B-19), deracoxib (B-20), rofecoxib (B-21), etoricoxib (MK-663; B-22), JTE-522 (B-23), BMS-347070, or a prodrug thereof.
• the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
• parecoxib (See, e.g. U.S. Patent No. 5,932,598), having the structure shown In B-24, which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib, B-19, (See, e.g., U.S. Patent No. 5,633,272), may be
• a preferred form of parecoxib is sodium parecoxib.
• etoricoxib (CAS RN 202409-33-4, MK-663, SC-86218, and in WO 98/03484).
• pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician. This amount can be a therapeutically effective amount.
• therapeutically-effective is intended to qualify the amount of each agent for use In the combination therapy, which will achieve the goal of Improvement in disease severity and the frequency of incidence over treatment of each agent by itself, and/or of amelioration of adverse side effects typically associated with alternative therapies.
• the combined preparations according to the present invention would be useful for the treatment of cancer.
• the subject methods and compositions of the present invention may be used for the treatment of
• neoplasia disorders including benign, metastatic and malignant neoplasias, and also including acral lentfgi ⁇ ous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus papilloma carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sar
• treating or “to treat” mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms.
• treatment Includes alleviation, elimination of causation of or prevention of cancer. Besides being useful for
• these combinations are also useful for treatment of mammals, including horses, dogs, cats, rats, mice, sheep, pigs, etc.
• subject for purposes of treatment includes any human or animal subject who is in need of the prevention of, or who has cancer, cardiovascular disease, or pain, inflammation and/or any one of the known inflammation-associated disorders.
• the subject is typically a mammal.
• mammal refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cattle, etc., Preferably, the mammal is a human.
• compositions may be admlnlstered to a patient in any acceptable manner that Is medically acceptable including orally, parenterally or with locoregional therapeutic approaches such as e.g. implants.
• Parenteral administration includes administering the constituents of the combined preparation by subcutaneous, intramuscular, intradermal, intramammary, intravenous injections and other administrative methods known in the art.
• Implants include intra artherial implants, for example, an intrahepatic artery implant.
• the administration of the constituents of the combined preparations of the present invention can be made simultaneously, separately or sequentially in any order.
• the present invention intends to embrace administration of a morpholinyl anthracycline derivative and a Cox-2 inhibitor in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and intends as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single dosage device having a fixed ratio of these active agents or in multiple, separate dosage devices for each agent, where the separate dosage devices can be taken together contemporaneously, or taken within a period of time sufficient
• the combined therapy of the present invention enhances the antitumoral effects of a morpholinyl anthracycline derivative and of the Cox-2 inhibitor and thus yields a more effective and less toxic treatment for tumors.
• the constituents of the combined preparations according to the invention can be administered to a patient in any acceptable manner that is medically acceptable including orally, parenterally, or with locoregio ⁇ al therapeutic approaches such as, e.g., implants.
• Oral administration includes administering the constituents of the combined preparation in a suitable oral form such as, e.g., tablets, capsules, lozenges, suspensions, solutions, emulsions, powders, syrups and the like.
• Parenteral administration includes administering the constituents of the combined preparation by subcutaneous, intravenous or intramuscular injections.
• Implants include intraarterial implants, for example an intrahepatic artery implant. Injections and implants are preferred administration routes for nemorubicin because they permit precise control of the timing and dosage levels used for administration.
• nemorubicin may be administered via the hepatic artery as an infusion; the appropriate dose of nemorubicin, preferably previously dissolved in saline solution, may be mixed with a suitable amount, for example an amount ranging from 1 ml to 100 ml
• LIPIODOL TM iodized oil
• the actual preferred method and order of administration of the constituents of the combined preparations of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the mo ⁇ holinyl anthracycline derivative being utilized, the particular pharmaceutical formulation of Cox-2 inhibitor being utilized, the particular cancer being treated, the severity of the disease state being treated, and the particular patient being treated.
• the dosage ranges for the administration of the combined preparations according to the Invention may vary with the age, condition, sex and extent of the disease in the patient and can be determined by one of skill in the art.
• the dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments, in a manner, which is conventional for any therapy, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions.
• a pharmaceutical composition of the present invention is directed to a composition suitable for the treatment of cancer.
• the pharmaceutical composition comprises a pharmaceutically acceptable carrier or excipient, and a mo ⁇ holinyl anthracycline derivative of formula (I), formula (II) or a pharmaceutically acceptable salt or metabolite thereof and a cyclooxygenase-2 selective inhibitor as active ingredients.
• compositions may also include stabilizers, anti-oxidants, colorants, and diluents.
• Pharmaceutically acceptable carriers and additives are chosen such that side effects from the pharmaceutical compound are minimized and the performance of the compound is not canceled or inhibited s to such an extent that treatment is ineffective.
• composition comprising a pharmaceutically acceptable carrier or excipient and, as an active ingredient, a mo ⁇ holinyl anthracycline derivative of formula 0 (I), formula (II) or a pharmaceutically acceptable salt or metabolite thereof and a Cox-2 inhibitor.
• compositions are s well known to people skill in the art of formulating compounds in a form of pharmaceutical compositions.
• compositions may routinely contain, e.g., pharmaceutically acceptable salts, buffering agents, preservatives and/or compatible carriers.
• pharmaceutically acceptable carrier refers to one or more compatible solid or liquid filler, diluent or encapsulating substances which are suitable for administration to mammals including humans.
• compositions suitable for parenteral or intrahepatic administration are formulated in a sterile form.
• the sterile composition thus may be a sterile solution or suspension in a non- toxic parenterally acceptable diluent or solvent.
• compositions for intrahepatic administration are formulated, for example, in a form, which remains selectively in a liver tumor after their injection through the hepatic artery; LIPIODOL TM may be a suitable carrier of 0 anticancer agents, which can be used for Intrahepatic administration.
• the amount of an active ingredient contained in the pharmaceutical composition according to the invention may vary quite widely depending upon many factors such as e.g. the administration route and the vehicle.
• the pharmaceutical composition of the invention may contain from 0.1 mg to 100 mg of nemorubicin; from 50 mg to 1000 mg of a Cox-2 inhibitor such as celecoxib or from 1 mg to 100 mg of valdecoxib or from 5 mg to 1000 mg of rofecoxib or from 10 mg to 1000 mg of etoricoxib.
• a further aspect of the present invention is to provide a method for the treatment of cancer in a subject in need of such a treatment, the method comprising administering to said subject a therapeutically effective amount of a morpholinyl anthracycline derivative of formula (I), formula (II) or a pharmaceutically acceptable salt or metabolite thereof and a Cox-2 inhibitor, In amounts effective to produce a synergistic anticancer effect.
• a mo ⁇ holinyl anthracycline derivative of formula (I), formula (II), a pharmaceutically acceptable salt or metabolite thereof may be administered simultaneously with a Cox-2 inhibitor, or the compounds may be administered sequentially, in either order. It will be appreciated that the actual preferred method and order of administration will vary according to, inter alia, the particular formulation of the morpholinyl anthracycline derivative being utilized, the particular formulation of the Cox-2 inhibitor being utilized, the particular tumor model being treated, and the particular host being treated.
• the amount of a mo ⁇ hollnyl anthracycline derivative, together with the amount of the cyclooxygenase-2 selective inhibitor or prodrug thereof, constitute an amount effective for the treatment of cancer.
• a mo ⁇ holinyl anthracycline derivative according to the invention e.g. nemorubicin
• course of therapy generally employed is from about 0.1 mg/m 2 to about 100 mg/m 2 of body surface area. More preferably, the course of therapy employed is from about about 1 mg/m 2 to about 1000 mg/m 2 of body surface area.
• the course of therapy generally employed is within a range of from about 0.01 to about 100 mg/day per kg of body weight of the subject, preferably within a range of from about 1 to about 20 mg/day per kg of body weight of the subject.
• The. present invention also provides a therapeutic kit comprising, in suitable container .
• a pharmaceutical formulation comprising mo ⁇ holinyl anthracycline derivative of formula (I), formula (II), a pharmaceutically acceptable salt or pharmaceutically active metabolite thereof and a pharmaceutical formulation comprising a Cox-2 inhibitor are present within a single container means or within distinct container means.
• kits comprises a pharmaceutical formulation of nemorubicin and a pharmaceutical formulation of Cox-2 inhibitor, within distinct container means.
• Kits according to the invention are intended for use in anticancer therapy as defined above.
• the superadditive antitumor effect of the combination preparation of the present invention can be shown by testing the in vitro cytotoxic activity and apoptotlc effect of nemorubicin and celecoxib on human tumor cell lines. Cytotoxicity is determined by microcufture tetrazolium dye assay. The apoptotic effect is tested by mo ⁇ hology and TUNEL assays. Cox-1 and Cox- 2 expression is demonstrable in all tested tumor cell lines. Cox-2 inhibition induced by celecoxib is apoptotic and reduces tumor cell proliferation. Nemorubicin is highly cytotoxic against all tested cell lines.
• the combination is determined by microcufture tetrazolium dye assay. The apoptotic effect is tested by mo ⁇ hology and TUNEL assays. Cox-1 and Cox- 2 expression is demonstrable in all tested tumor cell lines. Cox-2 inhibition induced by celecoxib is apoptotic and reduces tumor cell proliferation. Nemorubicin is highly cyto
• nemorubicin and celecoxib is supraadditive/synergistic, as assessed by isobolographic analysis. Supra-additive/synergistic is observed irrespective of treatment sequence.

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• 2004
  • 2004-03-04 WO PCT/EP2004/050251 patent/WO2004082689A1/en not_active Ceased
  • 2004-03-04 BR BRPI0408518-3A patent/BRPI0408518A/pt not_active Application Discontinuation
  • 2004-03-04 CA CA002519310A patent/CA2519310A1/en not_active Abandoned
  • 2004-03-04 AU AU2004222527A patent/AU2004222527A1/en not_active Abandoned
  • 2004-03-04 EP EP04717117A patent/EP1605951A1/de not_active Withdrawn
  • 2004-03-04 MX MXPA05009849A patent/MXPA05009849A/es unknown

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