Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/243—Platinum; Compounds thereof
• • 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
  • A61K31/28—Compounds containing heavy metals
  • A61K31/282—Platinum compounds
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• chemotherapy combined with radiation therapy is a known modality of treatment of neoplastic diseases
• tumours with ionising radiation, also referred to as radiation therapy, is extensively used in cancer therapy as it provides destruction of tumour cells together with inhibition of tumour cell growth, by a direct effect of radiation on
• Some anticancer compounds which are known as being cytotoxic per se, are also endowed with radiosensitisation activity as they are capable of inducing DNA radiation damage in response to ionizing radiation and hence of increasing the sensitivity of cacerous cells to the effect of the ionising radiation
• anthracycline de ⁇ vative which is a morpholinyl anthracycline derivative for use as radiosensitizer, administered in combination with radiation therapy, so that a synergishc effect can be revealed
• a preferred morpholinyl anthracycline derivative is the morpholinyl anthracycline de ⁇ vative of formula (I), more particularty in the form of its hydrochlo ⁇ de salt
• the term "metabolite” embraces all de ⁇ vatives resulted from an enzymatic biotransformation of a morpholinyl anthracycline derivative according to the invention The chemical reactions of enzymatic biotransformation are classified as ⁇ hase-1 or 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 obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid and the like, or with organic acids such as acetic acid, maleic acid, metthanesulfonic acid, ethanesulfonic acid, tarta ⁇ c acid, citric acid, succinic acid and the like, preferably hydrochloric acid
• inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid and the like
• organic acids such as acetic acid, maleic acid, metthanesulfonic acid, ethanesulfonic acid, tarta ⁇ c acid, citric acid, succinic acid and the like, preferably hydrochloric acid
• the morpholinyl anthracycline of formula (I) namely 3'desam ⁇ no-3'[2(S) methoxy-4- morphohnyl] doxorubicin, also known as nemorubicin, is a doxorubicin (DX) derivative different from classical anthracyc nes, obtained with the substitution of the -NH 2 at position 3' in the sugar moiety with a methoxymorpholinoyl group
• the term "nemorubicin” includes, unless otherwise specified, the morpholinyl anthracycline derivative of formula (I) and its pharmaceutically acceptable salts, especially the hydrochlonde salt
• Nemorubicin synthesized in the course of a research program aimed at identifying new anthracychnes with at least partially novel modes of action, effective against anthracycline resistant tumors and possessing broad spectrum of antitumor activity, was disclosed and claimed in Bargiotti et al , US patent No 4,672,057
• nemorubicin is significantly more potent in wv ⁇ than in vitro
• This observation suggested an in vivo metabolism of the drug to potent metabolite/s
• nemorubicin is metabolized to potent metabolite/s icrosomal 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 l iver lesions, even i n tumor types resistant to conventional chemotherapy
• Examples of identified metabolites of nemorubicin are compounds of the below formulae (III) to (VI)
• 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 compounds of formula (V) and (VI) may be earned out, for example, following the procedure disclosed in GB 2294495
• the compounds of formulae (III) to (VI) may also exist in the form of a pharmaceutically acceptable salt, in this case, preferred salts are hydrochloride salts.
• the present invention embraces combined preparations comprising a compound of the above formula (III), (IV) (V) or (VI) administered in combination with radiation therapy
• MX2 is active in vitro and in vivo on tumor cells resistant to anthracyclines and presenting the multi-drug resistant mdr phenotype No cross-resistance was observed on tumor cells resistant to CTX, L-PamA and cDDP
• MX2 is active in vivo after i p , i v and oral administration, with good antileukemic and antitumor activity on murine and human tumor models MX2 is highly lipophi c and less cardiotoxic than DXoxorubicin The major dose limiting factor of MX2 is myelosuppression
• a preferred combined preparation according to the invention comprises a morpholinyl anthracycline of formula (I) as defined above, a pharmaceutically acceptable salt thereof, especially hydrochloride salt, or a pharmaceutically active metabolite thereof, especially a metabolite selected from compounds of formulae (III) to (VI) as defined above, administered in combination with radiation therapy
• Preferred metabolites according to the present invention are metabolites of the morpholinyl anthracycline of formula (I) as defined above, particularly the compounds of formulae (III) to (VI) as defined above
• radiosensitisation activity it is intended the aforementioned capability of a compound to act as a radiosensitiser
• radiationosensitiser in its turn, it is intended a compound, which is capable of increasing/improving tumor cells destruction in response to ionizing radiation without an increase in toxicity
• Radiotherapy is the treatment of cancer with ionizing radiation
• Ionizing radiation deposits energy that injures or destroys cells in the area being treated (the “target tissue”) by damaging their genetic material, making it impossible for these cells to continue to grow
• Radiotherapy may be used, e g , to treat localized solid tumors, such as cancers of the skin, tongue, larynx, brain, breast, or ute ⁇ ne cervix It can also be used to treat leukemia and lymphoma (cancers of the blood-forming cells and lymphatic system, respectively)
• the term "ionizing radiation” is the term conventionally adopted in the therapeutic field of cancer treatment and includes electromagnetic radiation (roentgen and gamma radiation) and proton beam radiation therapy
• electromagnetic radiation roentgen and gamma radiation
• proton beam radiation therapy protocols refer to treatments ranging from 100 to 250 eV
• anticancer therapy refers to all types of therapies for treating cancers or neoplasms or malignant tumors found in mammals comprising humans
• 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 lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, ade ⁇ osquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangiocarcinoma, chondosarcoma, cho ⁇ od plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endomet ⁇ al hyperplasia, endometnal
• 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 amount is intended to qualify the amount of each agent for use in the combination therapy, which will achieve the goal of improvement in disease seventy 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
• combined preparations according to the invention may be used in anticancer therapy
• combined preparations of the invention may be useful for treating a liver cancer, for example a liver cancer pnma ⁇ ly confined to the liver such as, e g an hepatocellular carcinoma or a cholangiocarcinoma, or liver metastases
• the morpholinyl anthracycline derivatives 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 locoregional therapeutic approaches such as, e g , implants
• Oral administration includes administering the morpholinyl anthracycline derivatives 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 morpholinyl anthracycline derivatives of the combined preparation by subcutaneous, intravenous or intramuscular injections
• Implants include intra arterial implants, for example an intrahepatic artery implant
• Injections and implants are preferred administration routes because they permit precise control of the timing and dosage levels used for administration
• intrahepatic administration of the morpholinyl anthracycline denvahves of the combined preparation may be performed via the hepatic artery
• the morpholinyl anthracycline derivatives of the combined preparation may be administered to a patient with either a hepatic metastatic cancer, or with previously untreated primary liver carcinoma, via the hepatic artery directly into the lateral entry of an i v line inserted into the bung of an intrahepatic potacath or via a catheter inserted into the hepatic artery
• nemorubicin HCI may be administered via the hepatic artery as an infusion
• the appropriate dose of nemorubicin HCI preferably previously dissolved in saline solution
• may be mixed with a suitable amount for example an amount ranging from
• the actual preferred method and order of administration of the morpholinyl anthracycline derivatives of the combined preparation of the invention may vary according to, inter alia, the particular pharmaceutical formulation of the morpholinyl anthracycline derivatives as defined above 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 morpholinyl anthracycline derivatives 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 further aspect of the present invention is to provide a method for the treatment of a mammal including a human, suffenng from a cancer comprising administering to said mammal a morpholinyl anthracycline of formula (I), formula (II), a pharmaceutically acceptable salt or a pharmaceutically active metabolite thereof as defined above and radiation therapy in amounts effective to produce a synergishc anticancer effect
• a method of treating a tumor in a subject in need thereof comp ⁇ sing sequentially, separately or simultaneously administering
• the term "potentiating" means an increase in the beneficial activity or efficacy of the radiation therapy over that which would be expected from the radiation therapy alone, the morpholiny anthracycline derivative alone, or the sum of the activity of the radiation therapy when administered alone and the morpholiny anthracycline derivative when administered alone
• the combined administration of a morpholiny anthracycline derivative and radiation treatment means that the two are administered closely enough in time that the presence of one alters the biological effects of the other
• exposure to radiation therapy may either occur simultaneously whilst administering the medicament comprising the morpholinyl anthracycline derivative or, alternatively, sequentially in any order
• Simultaneous administration may be carried out by administering the morpholiny anthracycline derivative and radiation treatment at the same point in time but at different anatomic sites or using different routes of administration
• Sequential administration may be carried out by administering the morpholiny anthracycline derivative and radiation treatment at a different point in time, for example, the active compounds described herein may be administered orally, parenterally or via intrahepatic administration to a patient prior to receiving radiation therapy
• the schedule treatment first comprises administering the morpholiny anthracycline derivative to the patient, which only subsequently is subjected to radiation therapy exposure
• the schedule treatment first comprises administering the morpholiny
• a still further aspect of the present invention is to provide a method for lowenng the side effects caused by anticancer therapy with an anticancer agent in mammals, including humans, in need thereof, the method comprising administering to said mammal a combined preparation comprising a morpholinyl anthacycline of formula (I), formula (II), a pharmaceutically acceptable salt or a pharmaceutically active metabolite thereof as defined above and radiation therapy
• the present invention provides a method for the treatment of patients suffering from a primary or metastatic liver cancer
• a synergishc anticancer effect as used herein is meant the inhibition of the tumor growth, preferably the complete regression of the tumor without an increase in toxicity, administering an effective amount of the combination of a morpholinyl anthracycline of formula (I) or (II) as defined above and radiation therapy in amounts effective to produce a synergishc anticancer effect to mammals, including humans
• the morpholinyl anthracycline derivative may be also administered with additional antitumor agents such as, for instance, topoisomerase I or II inhibitors, e g CPT-1 1 , topotecan, 9-am ⁇ no-camptothec ⁇ n, 9- nitro-camptothecin, 10,11-methylened ⁇ oxy-camptothec ⁇ n, doxorubicin, daunorubicm, epirubicin, nemorubicin, idarubicin, etoposide, teniposide, mitoxanthrone, losoxantrone, amsac ⁇ ne, actinomycin D, alkylatmg agents, e g melphalan, chlorambucil, mechlorethamine, cyclophosphamide, ifosfamide, busulfan, carmusttne, lormustine, semustine, fotemustine, decarbazine, tem
• the use of a morpholinyl anthracycline derivative with radiation therapy also comprises the administration of a platinum alkylating agent, e g cisplatin, carboplatin, oxaliplatm, nedaplatin or lobaplatm, more preferably cisplatin
• a platinum alkylating agent e g cisplatin, carboplatin, oxaliplatm, nedaplatin or lobaplatm, more preferably cisplatin
• a combined preparation comp ⁇ sing a morpholinyl anthracycline derivative having formula (I), formula (II), a pharmaceutically acceptable salt or a pharmaceutically active metabolite thereof, administered in combination with radiation therapy which further comprises administering a therapeutically effective amount of a platinum alkylating agent, especially cisplatin
• the 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 1 mg/m 2 to about 1000 mg/m 2 of body surface area
• the anticancer therapy of the present invention is suitable for treating, e g breast, ovary, prostate, lung, colon, kidney, stomach, pancreas, liver, melanoma, leukemiae and central nervous system tumors in mammals, including humans, in particular it is suitable for treating a liver cancer
• the effect of the combined administration of a morpholinyl anthracycline derivative of formula (I), formula (II), a pharmaceutically acceptable salt or a pharmaceutically active metabolite thereof as defined above and radiation therapy is significantly increased (more than additive/synergic effect) in experimental tumor models
• the combined therapy of the present invention enhances the anticancer effects of the morpholinyl anthracycline (I), formula (II), a pharmaceutically acceptable salt or a pharmaceutically active metabolite thereof or (I) as defined above and of radiation therapy and thus yields the most effective treatment for cancers
• SR Sensitization Ratio

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• 2004
  • 2004-03-03 WO PCT/EP2004/050246 patent/WO2004082579A2/en not_active Application Discontinuation
  • 2004-03-03 RU RU2005132175/15A patent/RU2005132175A/ru not_active Application Discontinuation
  • 2004-03-03 EP EP04716607A patent/EP1603575A2/en not_active Withdrawn
  • 2004-03-03 MX MXPA05009851A patent/MXPA05009851A/es unknown
  • 2004-03-03 CA CA002519289A patent/CA2519289A1/en not_active Abandoned
  • 2004-03-03 BR BRPI0408494-2A patent/BRPI0408494A/pt not_active Application Discontinuation
  • 2004-03-03 AU AU2004222526A patent/AU2004222526A1/en not_active Abandoned
• 2005
  • 2005-09-20 NO NO20054349A patent/NO20054349L/no unknown

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