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• • 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
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates to the use of a combination of a bioresponse modifier and a chemotherapeutic agent in the potentiation of chemotherapy and in the treatment of solid tumors.
• Cancer chemotherapy for solid tumors has historically been focused on cytotoxic drugs that target essential metabolic processes (anti-metabolites) or general toxins (alkylating agents) that interfere with multiple metabolic processes.
• Antibiotic based drugs doxorubicin, mitoxantrone, mitomycin C, etc.
• microtubule active (taxanes, vinca alkaloids) compounds target structurally essential components of the cell, rendering these compounds generally toxic as well.
• U.S. Patent 5,312,831 disclose urethanes and ureas which induce cytokine production, that are useful in restoring neutrophils after cancer chemotherapy, radiation therapy, bone marrow transplantation, or infections, and are useful in the treatment of cancer, AIDS, aplastic anemia, myelodysplastic syndrome, infectious diseases, and the enhancement of the immune response.
• U.S. Patent 4,666,890 discloses a synthetic tripeptide which has been reported to have activity as an immunomodulator, for use as an antitumor agent rather than as an adjuvant to chemotherapy.
• the reported cell-wall components and their synthetic analogs are all peptides incorporating a D-glutamic acid (D-Glu) moiety q-linked to either lysine (Lys) or diaminopimelic acid (A2pm), with additional peptide bonds or fatty acyl groups flanking the two ends.
• D-Glu D-glutamic acid
• Lys lysine
• A2pm diaminopimelic acid
• This invention provides a method of treating solid tumors which comprises administering an effective amount of a combination of (1) a bioresponse modifier and (2) a chemotherapeutic agent.
• This invention also provides a method of potentiating the effects of a chemotherapeutic regimen in a mammal in need of treatment with such regimen which comprises administering a bioresponse modifier in addition to a chemotherapeutic regimen.
• a bioresponse modifier and a chemotherapeutic agent includes the administration of one or more agents of each category; thus, for example, the term a chemotherapeutic agent can include the administration of two chemotherapeutic agents.
• Treating is defined as providing palliative treatment, or inhibiting the growth or eradicating the solid tumor for which treatment is administered.
• a bioresponse modifier is an agent which activates the body's innate immune system, and typically includes cytokine inducers and immune adjuvants.
• Cytokine inducers are agents which induce the production of cytokines, and include cytokines such as IL-1, TNF; natural products such as muramyl dipeptide, lipopolysaccaride and beta-glucan; and synthetic cytokine inducers such as those disclosed in U.S. Patents 5,312,831, and 4,666,890, the disclosures of which are hereby incorporated by reference. Cytokine inducers are the preferred bioresponse modifiers of this invention.
• cytokine inducers are those disclosed in U.S. Patent 5,312,831(EP 652228) of Formula I, having the structure:
• R is selected from the group consisting of hydrogen, a substituted or unsubstituted (C,-C 20 ) alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a vinyl group, an acetylene group, a substituted or unsubstituted amino group, a substituted or unsubstituted acylamino group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkylgroup, a substituted or unsubstituted aryl- oxy group, a substituted or unsubstituted alkoxyaryl group, a substituted or unsubstituted alkoxyaralkyl group and a substituted or unsubstituted mono- cyclic or bicyclic heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting
• R a and R 3 are independently selected from hydrogen, substituted or unsubstituted (C,-C 6 ) alkyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkoxyaralkyl, vinyl, acetylene and a sustituted or unsubstituted monocyclic or bicyclic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms provided that, in the case of R 3 , the hetero atoms in said heterocycle are not directly bonded to the —CH— group of the — CH— X— moiety; R j , R b and R c are independently selected from carboxy or protected carboxy, carboxy or
• R 4 is H or an amino protecting group; wherein the substituents in the aforementioned substituted alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, aryl, aralkyl, aryloxy, alkoxyaryl, alkoxyaryalkyl and heterocyclic groups are selected from the group consisting of halogen, hydroxyl, lower alkyl, lower alkoxy, aryloxy, aralkyloxy, amino, mono- or di-loweralkylamino, arylamino, aralkylamino, carboxyl, formyl, lower alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, loweralkylthio, arylthio, aralkylthio, arylsulfinyl, arylsulfinyl, aralkylsulfinyl, lower alkylsulfonyl, aryls
• Formula I are provided in US Patent 5,312,831 and EP 652228.
• the cytokine inducers of Formula I may contain one or more asymmetric carbons atoms; in such cases, the compounds of Formula I cover the individual diasteromers, the racemates, and the individual R and S entantiomers thereof.
• the (C,-C 20 )alkyl group may be a straight chain or branched lower alkyl group having from 1 to 20 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert- butyl group, a pentyl group, a neopentyl group, an isopentyl group, a hexyl group, an isohexyl group and so forth.
• the cycloalkyl group may be a cycloalkyl group having from 3 to 6 carbon atoms such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
• the cycloalkylalkyl group may be a cycloalkylalkyl group having from 4 to 12 carbon atoms such as a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, 1-cyclopropylethyl group, a 2-cyclopropylethyl group, a 2-cyclopropylethyl group, a 1-cyclobutylethyl group, a 2-cyclobutylethyl group, a 1-cyclopentylethyl group, a 2-cyclopentylethyl group, a 1-cyclohexylethyl group, a 3-cyclohexylpropyl group, a 3 cyclopentylpropyl group, a 4-cyclohexylbutyle group, a 4-cyclopentylbutyl group, a 4-cyclopentylpentyl group,
• the acylamino group may be an acylamino group in which the acyl moiety is derived from an acid such as organic carboxylic acid or carbonic acid, each of which more particularly includes an aliphatic, an aromatic and/or heterocyclic group in its molecule.
• aliphatic acyl groups having an acyl group derived from an aliphatic acid and includes: alkanoyl (e.g formyl, acetyl, propionyl, butyryl, iso- butyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, ⁇ -ethyl-hexanoyl, heptanoyl, lauroyl, stearoyl, docosanoyl, a group of the formula: CH 3 (CH 2 ) 31 CO, [CH 3 (CH 2 ) 2l ] 2 CHCO, [CH 3 (CH 2 ) 15 ] 2 CHCO, CH 3 (CH 2 ) 41 CO, etc); lower alkoxy-carbonyl (e.g methoxy- carbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, t-pentoxycarbonyl, etc.) and the like.
• the acyl moiety may also be an aromatic acyl meaning an acyl group derived from an acid having a substituted or unsubstituted aryl group, in which the aryl group may include phenyl, tolyl, xylyl, naphthyl and the like, and suitable examples thereof are illustrated as follows: aroyl (e.g benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.); aralkoxycarbonyl (e.g benzyloxycarbonyl, benz- hydroloxycarbonyl, trityloxycarbonyl, ⁇ -naphthyl-methoxycarbonyl, etc.) and the like.
• aroyl e.g benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.
• aralkoxycarbonyl e.g
• the acyl moiety may also be a heterocyclic acyl group meaning an acyl group derived from an acid having a heterocyclic group and includes: heterocyclic carbonyl, in which the heterocycle moiety is 5 to 6 membered heterocycle containing at least one to four heteroatoms selected from nitrogen, oxygen and sulfur (e.g thienoyl, furoyl, pyrrolecarbonyl, 5-oxo-2-pyrrolidinecarbonyl, nicotinoyl, etc.) and the like.
• heterocyclic acyl group meaning an acyl group derived from an acid having a heterocyclic group and includes: heterocyclic carbonyl, in which the heterocycle moiety is 5 to 6 membered heterocycle containing at least one to four heteroatoms selected from nitrogen, oxygen and sulfur (e.g thienoyl, furoyl, pyrrolecarbonyl, 5-oxo-2-pyrrolidinecarbonyl, nicotinoyl, etc.) and the like.
• the aryl group may be an aryl group having from 6 to 15 carbon atoms such as a phenyl group, a biphenylyl group, a 1 -naphthyl group or a 2-naphthyl group.
• the aralkyl group may be an aralkyl group having from 7-15 carbon atoms such as a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a
• the aryloxy group may be an aryloxy group having from 6-15 carbon atoms such as a phenoxy group, a biphenyloxy group, a 1-naphthyloxy group, or a 2- naphthyloxy group.
• the alkoxyaryl or alkoxyaralkyl group may be an alkoxyaryl or alkoxyaralkyl group having from 6 to 21 carbon atoms such as a benzoyl group, or an alkoxyphenylmethyl group.
• the monocyclic or bicyclic heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms may be a heterocyclic group having from 4-15 carbon atoms such as a pyrrolyl group, a furyl group, a thienyl group, a pyridyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an isoxazolyl group, an oxazolyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, an indolyl group, a quinolyl group, an isoquinolyl group, a phthalazinyl group, a naphthidinyl group, a quinoxalinyl group, a quinazolinyl group, a 1,4-benzodioxany
• the substituents in the aforementioned groups (a)-(i) may be halogen atom such as a chlorine atom, a fluorine atom or a bromine atom, a hydroxyl group; a lower alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group; a lower alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group or a tert-butoxy group; an aryloxy group such as a phenoxy group, as 1-naphthyloxy group or a 2-naphthyloxy group; an aralkyloxy group such as a benzyloxy group,
• lower alkyl means a C,-C 6 alkyl group.
• a protecting group for the protected carboxy or protected carboxyloweralkyl include any conventional protecting groups for carboxy groups as routinely used by those skilled in the art of peptide and amino acid chemistry such as those found in T. Green, "Protecting Groups in Organic Synthesis", J Wiley and Sons, 1981. These include silyl esters, aliphatic esters, and aromatic esters such as trimethylsilyl, t-butyldimethysilyl, acetyl, benzoyl, and the like.
• a protecting group for the protected amino group includes any conventional protecting group for amino groups as routinely used by those skilled in the art of peptide and amino acid chemistry such as those found in T. Green, supra pp 218-287.
• a suitable protecting group is chosen such that conditions for its removal are compatible with other structural features of the compound.
• Suitable protecting groups include acyl groups such as tert-butoxycarbonyl or benzyloxycarbonyl and the like.
• R is selected from the group consisting of a substituted or unsubstituted (C,-C 20 ) alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted alkoxyaryl group, and a substituted or unsubstituted alkoxyaralkyl group wherein the aryl moiety in the foregoing groups is selected from substituted or unsubstituted phenyl; R a and R 3 are indepenently selected from hydrogen, and substituted or unsubstituted (C,-C 6 )a ⁇ kyl;
• X is oxygen or nitrogen; and R 4 is H or an amino protecting group.
• R is selected from the group consisting of a (C 4 -C 14 )alkyl group, a cycloalkyl group, a (C 2 -C 8 )alkyl substituted cycloalkyl group, a phenyl group, a benzyl group, a (C 4 -C 8 )alkylphenyl group, and a (C,-C 6 )alkyl- or alkoxy- phenylmethyl group;
• R a and R 3 are independently selected from hydrogen and (C,-C 6 )alkyl;
• R 2 , R b and R c are independently selected from carboxy or protected carboxy, carboxy or protected carboxyloweralkyl and carboxyamide;
• X is oxygen or nitrogen
• R 4 is H or an amino protecting group.
• R is selected from the group consisting of an n-hexyl group, a 4-n- pentylcyclohexyl group;
• R, and R 3 are independently selected from hydrogen or methyl; R 2 , R b and R c are carboxy;
• X is oxygen or nitrogen
• R 4 is H.
• R 3 is methyl, and R, and R 2 are hereinbefore defined.
• R is methyl
• R b , R c and R 4 are as hereinbefore defined.
• R 3 and R are methyl
• X is oxygen
• R b , R c , R R 2 , R 4 are hereinbefore defined.
• the cytokine inducer is [R-(R*,R*)]-N-[(R)-6- carboxy-N 2 -[[2-carboxy-l-methyl-2-[(l-oxoheptyl)amino]ethoxy]carbonyl]-L-lysyl]- alanine or a pharmaceutically acceptable salt thereof (a compound of Formula I), which is disclosed as Example 28 of U.S. Patent 5,312,831.
• U.S. Patent 5,312,831 discloses several standard pharmacologic test procedures which will enable one skilled in the art to evaluate whether compounds are bioresponse modifiers. For example, the test procedures in col. 16-17, evaluate the induction of IL-6, CSF, and G-CSF production.
• the chemotherapeutic agent is a microtubular agent or a macrophage activating agent.
• Microtubular active compounds are defined as compounds that destabilize microtubules either by preventing polymerization of the protein tubulin (e.g., vincristine) or by preventing the depolymerization of tubulin (e.g., taxanes).
• the assembly and disassembly of microtubules is a dynamic process influenced by tubulin binding proteins and protein phosphorylation (kinases).
• Microtubular active compounds include taxanes, such as paclitaxel or docetaxel, vincristine, vinblastine, vinorelbine, and the like.
• Macrophage activating agents are those compounds which activate macrophage activity, such as adriamycin, doxirubicin, and similar anthracenediones and anthracyclines, cisplatin, carboplatin, mitomycin C, bleomycin, and the like. It is preferred that the chemotherapeutic agent is paclitaxel or carboplatin, or a combination of both.
• the microtubular agents or macrophage activating agents of this invention are either commercially available or can be prepared by standard procedures in the published literature.
• mice Balb-c nu/nu female mice were obtained from Charles River Laboratories at 6- 8 weeks of age and used experimentally at 8-10 weeks of age.
• the human non small- cell lung carcinoma (NSCLC) line H-157 was obtained from the American tissue culture collection (ATCC) (Bethesda, MD). Cells were grown in RPMI medium with 10% fetal bovine serum.
• mice were injected subcutaneously with 7.5 x 10 6 H-157 NSCLC tumor cells.
• Tumors were allowed to develop until they reached a size of 80-150 mg. Tumor size was determined using vernier calipers to measure length (1) and width (w). The tumor volume was estimated using the formula 1 x w 2 /2. The volume in mm 3 can be converted to milligrams directly assuming unit density. Seven days after injection, mice were randomized (day 0) into groups of 10 with a mean tumor mass of 100 mg.
• Treatment groups received paclitaxel (30 mg/kg) on day 0 and either vehicle or [R- (R*,R*)]-N-[(R)-6-Carboxy-N 2 -[[2-carboxy-l-methyl-2-[(l-oxoheptyl)amino]ethoxy] carbonyl] -L-lysyl]-alanine (100 ⁇ g/kg) on days 1 and 8.
• a data are from 5 independent evaluations (mean ⁇ standard deviation) in which there were 10 mice/group in each evaluation.
• Treatment groups received paclitaxel (30 mg/kg) on day 0 and either vehicle or CI (100 ⁇ g kg) on day 1 and day 8.
• cancer patients with late stage disease were given a dose of [R-(R*,R*)]-N-[(R)-6-carboxy-N 2 -[[2-carboxy-l-meth- yl-2-[(l-oxoheptyl)amino]ethoxy]carbonyl]-L-lysyl]-alanine (cycle 0) approximately 7 days before the first round of chemotherapy (carboplatin and paclitaxcel).
• the combination regimen can be given simultaneously or can be given in a staggered regimen, with the bioresponse modifier being given at a different time during the course of chemotherapy. Therefore, the term combination does not necessarily mean administered at the same time or as a unitary dose.
• the regimen in the clinical study typifies a therapeutically useful regimen, in which patients received a bioresponse modifier before receiving the first course of chemotherapy.
• the course of chemotherapy is repeated several weeks later, and in this case, the bioresponse modifier was administered one or more days after the administration of the second course of chemotherapy. This course of staggered administration can be continued throughout the treatment period.
• the components of the combination can be formulated into a unitary dosage form, for simultaneous administration, however, it is anticipated that the components of the combinations will be formulated for separate administration.
• Formulations for specific chemotherapeutic agents are well known in the art (and most used will typically be commercially available or already formulated for use in clinical trials), with such agents typically administered intraveneously or orally; however, as each agent and patient varies, the chemotherapeutic agents may also be administered by parenteral injection, rectally, vaginally, transdermally, subcutaneously, topically, intranasally, or by direct infusion to the site of the lesion.
• the bioresponse modifiers of this invention may also be administered orally, intraveneously, parenterally, rectally, vaginally, transdermally, subcutaneously, topically, intranasally, or by direct infusion to the site of the lesion.
• bioresponse modifiers can be formulated according to standard literature methodology.
• formulations for the compounds of Formula I and [R-(R*,R*)]-N-[(R)-6- carboxy-N 2 -[[2-carboxy-l-methyl-2-[(l-oxoheptyl)amino]ethoxy] carbonyl]-L-lysyl]- alanine are provided in U.S. Patent 5,312,831.
• Bioresponse modifiers and chemotherapeutic agents which are not commercially available or available in clinical trials (or in which it is undesirable to use such existing formulations) may be formulated neat or may be combined with one or more pharmaceutically acceptable carriers for administration.
• pharmaceutically acceptable carriers for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solution or suspension containing from about 0.05 to 5% suspending agent in an isotonic medium.
• Such pharmaceutical preparations may contain, for example, from about 0.05 up to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
• Formulation for tablet or capsule administration may include solid carriers including starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
• Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. These components of the combination may also be administered parenterally or intraperitoneally.
• Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparation contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
• the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• chemotherapeutic agents and bioresponsive modifiers will be adjusted during the course of treatment, according to patient response to treatment and toxicity inherent in standard chemotheropeutic regimens. For example, the dosage of chemotherapeutic agents is typically lowered upon observation of myelosuppression or impaired hepatic function. As a starting dosage, it is anticipated that the initial dosages of chemotherapeutic agents will be the dosages which would be used absent combination with a bioresponse modifier.

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• 2000
  • 2000-09-12 AU AU73736/00A patent/AU7373600A/en not_active Abandoned
  • 2000-09-12 JP JP2001523030A patent/JP2003509383A/ja active Pending
  • 2000-09-12 EP EP00961841A patent/EP1214092A2/en not_active Withdrawn
  • 2000-09-12 CN CN00812921A patent/CN1391484A/zh active Pending
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