Classifications

• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
  • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/007—Pulmonary tract; Aromatherapy
  • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

• the invention relates to methods, compounds, compositions and kits for the treatment and/or prevention of cancer.
• Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.
• the typical hallmarks of cancer include abnormal cell growth and division, avoidance of programmed cell death, limitless number of cell divisions, increased blood vessel formation, and invasion of tissue and formation of metastases.
• Typical approaches to the treatment of cancer have historically included radiation therapy, chemotherapy, immunotherapy, and surgery.
• the present invention provides a method of treating, preventing or minimising progression of cancer in a subject comprising administering a therapeutically effective amount of a compound disclosed herein to a subject, thereby treating, preventing or minimising progression of cancer in the subject.
• the present invention provides a method of treating, preventing or minimising progression of cancer in a subject comprising administering a therapeutically effective amount of a compound described herein to a subject, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof.
• a method of treating, preventing or minimising progression of cancer in a subject comprising the administration of a therapeutically effective amount of a compound described herein to the respiratory tract of a subject, thereby treating, preventing or minimising progression of cancer in the subject.
• the compound is administered by inhalation.
• the compound is a compound as defined by any one of formulas (I), (IA1), (IA2), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII) and (XIX) (collectively referred to herein as formulas (l)-(XIX)).
• the compound may comprise moiety A selected from A1' and A2 as defined herein and PEG, wherein the moiety A and PEG are linked by a glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue.
• the compound may comprise or consist of partial structure A1Y' or A2Y':
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2;
• R, R 13 and R 18 are each independently H or C 1 -C 6 aliphatic;
• L 1 and L 2 are each independentlyC 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C 2 -C 20 heteroaliphatic
• a 2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , and L 3 is optionally substituted; and A1Y' or A2Y' is covalently linked to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG polyethylene glycol
• the compound is selected from any of compounds A101 -A114 and A201-A232.
• a compound comprising moiety A selected from A1' and A2 as defined herein and a polyethylene glycol (PEG), wherein the moiety A and PEG are linked by a glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue; and/or
• the present invention provides a method of treating, preventing or minimising progression of cancer in a subject comprising the steps of:
• the present invention further provides a method of increasing survival of a subject having cancer comprising administering a therapeutically effective amount of any compound described herein to a subject, thereby increasing survival of the subject having cancer.
• the present invention further provides a method of minimising, reducing or preventing growth of a tumour in a subject having cancer comprising administering a therapeutically effective amount of any compound described herein to a subject, thereby minimising, reducing or preventing growth of a tumour in the subject having cancer.
• the methods described herein further comprise identifying a subject having cancer.
• the cancer may be pre-cancerous or non-metastatic.
• the cancer may be malignant or metastatic.
• the present invention further provides a method of minimising, reducing or preventing metastasis in a subject having cancer comprising administering a therapeutically effective amount of any compound described herein to a subject, thereby minimising, reducing or preventing metastasis in the subject having cancer.
• method minimises, reduces or prevents metastasis to the lung.
• the invention further provides a method of minimising, reducing or preventing metastasis in a subject having cancer comprising:
• the present invention further provides a method of minimising, reducing or preventing growth of a tumour in at least one site distant from the site of the primary tumour in a subject comprising administering a therapeutically effective amount of any compound described herein to a subject, thereby minimising, reducing or preventing minimising, reducing or preventing growth of a tumour in at least one site distant from the site of the primary tumour in the subject.
• the present invention further provides use of any compound disclosed herein in the preparation of a medicament for treating, preventing or minimising progression of cancer in a subject.
• the medicament is for any of the methods described herein including the following:
• any medicament described herein is suitable for administration intraperitoneally, intratumorally, topically, orally, intravenously, subcutaneously or intramuscularly.
• any medicament described herein is suitable for administration intravenously, or to the respiratory tract, preferably by inhalation.
• the medicament may be suitable for formulation as a nasal spray or as nasal drops.
• the present invention further provides any compound disclosed herein for use in treating, preventing or minimising progression of cancer in a subject.
• any compound disclosed herein is for use in any of the methods described herein including the following:
• the compound for use is suitable for administration intraperitoneally, intratumorally, topically, orally, intravenously, subcutaneously or intramuscularly.
• the compound for use is suitable for administration intravenously, or to the respiratory tract, preferably by inhalation.
• the compound may be suitable for formulation as a nasal spray or as nasal drops.
• the present invention further provides use of any compound disclosed herein for use in treating, preventing, or minimising progression of cancer in a subject.
• use of any compound disclosed herein is for: - increasing survival of a subject having cancer;
• any compound disclosed herein is administered once. In another embodiment, any compound disclosed herein is administered two, three, four or more times to the subject.
• any compound disclosed herein may be administered by any known administration routes in the art including locally or systemically.
• administration routes in the art including locally or systemically.
• any compound disclosed herein is administered intravenously, intratumorally or by inhalation.
• the amount of any compound disclosed herein may be administered may be in the range of about 250 nmoles/kg body weight/dose to 0.005 nmoles/kg body weight/dose.
• the range is about 250 nmoles/kg body weight/dose to 0.05 nmoles/kg body weight/dose.
• the body weight/dose range is about 250 nmoles/kg, to 0.1 nmoles/kg, about 50 nmoles/kg to 0.1 nmoles/kg, about 5 nmoles/kg to 0.1 nmol/kg, about 2.5 nmoles/kg to 0.25 nmoles/kg, or about 0.5 nmoles/kg to 0.1 nmoles/kg body weight/dose.
• the amount is at, or about, 250 nmoles, 50 nmoles, 5 nmoles, 2.5 nmoles, 0.5 nmoles, 0.25 nmoles, 0.1 nmoles or 0.05nmoles/kg body weight/dose of the compound.
• the amount of any compound disclosed herein may be administered may be in the range of about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 .0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100mg/kg or more.
• the cancer is selected from the group consisting of breast cancer, colorectal cancer, adenocarcinomas, mesothelioma, bladder cancer, prostate cancer, germ cell cancer, hepatoma/cholongio carcinoma, neuroendocrine cancer, pituitary neoplasm, small round cell tumour, squamous cell cancer, melanoma, atypical fibroxanthoma, seminomas, nonseminomas, stromal leydig cell tumours, Sertoli cell tumours, skin tumours, kidney tumours, testicular tumours, brain tumours, ovarian tumours, stomach tumours, oral tumours, bladder tumours, bone tumours, cervical tumours, esophageal tumours, laryngeal tumours, liver tumours, lung tumours, vaginal tumours or Wilm's tumour.
• the cancer is melanoma, breast, fibrosarcoma or colon cancer.
• the cancer may be immunogenic (immune cell rich) or poorly immunogenic (immune cell poor).
• the compound to be administered may be any one of compound 1 , compound 2, compound 3, compound 4, compound 5, compound 6, compound 9, compound 10, compound 11 , compound 12, compound 13, compound 14, compound 15, compound 16, compound 17 as described herein.
• the compound to be administered may be compound A108, A102, or A103.
• any compound described herein may be administered in a composition.
• the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.
• the composition may be formulated for respiratory, intraperitoneal, intratumoural or intravenous administration to the subject. In other words, the composition is suitable for administration intratumourally, intravenously or to the respiratory tract.
• the composition comprises, consists essentially, or consists of any compound described herein, and a pharmaceutically acceptable carrier, diluent or excipient.
• the composition is formulated for administration to the respiratory tract, for example by inhalation or intranasally.
• the composition is formulated for administration as a nasal spray or as nasal drops.
• any compound described herein may be administered as the only active agent, for example only pharmaceutically active agent.
• the compound may be administered free of any other compounds for treating, preventing or minimising the progression of cancer.
• the present invention provides a method of treating, preventing or minimising progression of cancer in a subject consisting, or consisting essentially of administering a therapeutically effective amount of any compound disclosed herein to a subject, thereby treating, preventing or minimising progression of cancer in the subject.
• any compound described herein is not administered with, or a composition comprising a compound described herein does not contain: an antigen; a peptide antigen; or a T-helper antigen.
• the composition may not activate a cell mediated immune response.
• any compound described herein is not administered with a cell penetrating peptide.
• the compound does not comprise an electrostatically associated charged antigen.
• FIG. 1 Compound 1 has anti-tumour activity in the MC38 model.
• B. Corresponding mean tumour growth curves (mean ⁇ SEM.; n 10 for all groups).
• C. Kaplan-Meier survival curves (n 10 for all groups; Log rank test).
• FIG. 1 Compound 1 has anti-tumour activity in the B16F10 model.
• FIG. 4 Systemic delivery of compound 1 inhibits spontaneous 4T1.2 breast cancer metastasis.
• C. Combined analysis of experiment 1 and 2 (mean ⁇ SEM.; n 16 in each group; student's t-test).
• Compound A108 has anti-tumour activity in the immune cell-rich MC38 model.
• Compound A108 administered via the i.t or i.p route has anti-tumour activity in the immune cell-rich MC38 model in large tumours.
• A) Demonstrates the anti-tumour effect of compound A108, over the treatment period when the compound is administered i.t.
• B Demonstrates the anti-tumour effect of compound A108, over the treatment period when the compound is administered i.p. 2-way ANOVA with Tukey's multiple comparison test. Treatment groups compared to each other within a specific time-point.
• Compound A108 yields a better effect on tumour growth than Pam3CysSK4 over 12 days in the MC38 large tumour model.
• D. Compound A108 yields an effect on tumour growth in the MC38 large tumour model that is at least as comparable as the effect of commercially available anti-PD1 antibodies.
• FIG. 7 Compound A108 is effective in the WEHI-164 cancer model when administered intraperitoneally or intravenously.
• FIG. 8 Systemic delivery of compound A108 inhibits growth rate of EMT6.5 tumours.
• A) EMT6.5 tumour growth rates in mice treated with compound A108 or vehicle control n 6 mice per therapeutic arm. Differences between tumour growth rate was evaluated by linear regression; B) Primary tumour weight at experimental end point.
• C) Evaluation of lung metastatic burden by RTQ-PCR assay. N 6 mice per therapeutic arm. Unpaired, two-sided t-tests were performed to determine significance; P values as indicated.
• Statistic Log-rank (Mantel-Cox). The number in ( ) indicates the number of tumor free mice.
• the present inventors have unexpectedly found that when the compounds disclosed herein are administered to a subject with cancer, the treatment is highly effective, including at a number of doses and in a number of models of cancer. Specifically, the administration of a compound disclosed herein provides for one or more of:
• epithelial mammary carcinoma that has characteristics of triple-negative breast cancer
• the inventors also describe herein the utility of a number of different compounds in treating cancer including:
• the inventors identify the therapeutic utility of the compounds described herein in treating a number of different types of cancer, at different doses, with various routes of administration.
• Any of the compounds described herein may have utility in the treatment of cancer including cancer metastasis.
• any compound described herein also includes a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
• the compounds described herein may demonstrate substantial stability in solution. This solution stability may be observed by storing solutions of the compounds under ambient storage conditions (eg at 25°C) or under accelerated degradation stability (eg at 40°C) for at least about 14 days.
• the compound may be a compound of formula (I):
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; and in moiety A2: b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, such as from 2 to 5, provided that: the sum of b, v, and w is at least 3; and the sum of b and w is from 0 to 7; Z 1 and Z 2 are each independently selected from the group consisting of -O-, -NR-,
• R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 ,and R 17 are each independently H or C 1 -C 6 aliphatic;
• R, R 13 and R 18 are each independently H or C 1 -C 6 aliphatic;
• L 1 and L 2 are each independently C 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C 2 -C 20 heteroaliphatic
• a 2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , and L 3 is optionally substituted;
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl
• B comprises or consists of Polyethylene Glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG Polyethylene Glycol
• the compound may be a compound of formula (IA1):
• A comprises or consists of moiety A1 : wherein each g is independently 10, 11 , 12, 13, 14, 15, 16, 17 or 18; z is 1 or 2;
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond;
• B comprises or consists of Polyethylene Glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG Polyethylene Glycol
• g is an integer from 12 to 16.
• g 14.
• the compound may be a compound of formula (IA2):
• R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 are each independently H or C 1 -C 6 aliphatic;
• R, R 13 and R 18 are each independently H or C 1 -C 6 aliphatic;
• L 1 and L 2 are each independently C 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C 2 -C 20 heteroaliphatic;
• a 2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , and L 3 is optionally substituted;
• B comprises or consists of Polyethylene Glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG Polyethylene Glycol
• v is an integer selected from 2, 3, 4 or 5. In some embodiments, v is 2 or 3. In some embodiments, v is 2.
• R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are H.
• R and R 13 are each H.
• w is an integer selected from 1 -7. In some embodiments, w is 1 .
• b is 0.
• the sum of b and w is from 1 to 7.
• b may be an integer selected from 0-7 and w may be an integer selected from 1 -7, preferably 1 .
• b is 0, w is 1 and v is 2.
• R 18 is H.
• L 1 and L 2 are independently selected from C 5 -C 21 aliphatic or C 4 - C 20 heteroaliphatic. In some embodiments, L 1 and L 2 and independently selected from C 10 -C 18 aliphatic or C 10 -C 18 heteroaliphatic. In some embodiments, L 1 and L 2 are independently selected from C 14 -alkyl and C 15 -alkyl.
• X is S.
• R 6 and R 7 are each H.
• R 18 and R 19 are each H.
• the invention provides a compound of formula (I) wherein: v is an integer selected from 2 to 5; b is 0;
• R x , R y , R 13 , R 14 , R 15 , R 16 , and R 17 are H;
• w is an integer selected from 1 to 7;
• L 1 and L 2 and independently selected from C 10 -C 18 aliphatic or C 10 -C 18 heteroaliphatic.
• the invention provides a compound wherein v is 2; b is 0; w is 1 ; the sum of v, b and w is 3; the sum of b and w is 1 ; z is 1 ;
• R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 at each instance of b, v, w, and z are each H;
• R and R 13 are each H;
• R 18 is H;
• L 1 and L 2 and independently selected from C 10 -C 18 aliphatic or C 10 -C 18 heteroaliphatic.
• any embodiment of a substituent described herein including substituents R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , z, X, g, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , Z 1 , Z 2 , b, v, w, n, m, p, q, R 3 , L, t, k and h, is intended to apply to any instance of that substituent for any compound described herein, including compounds of formulas (l)-(XIX).
• the compound may be a compound of formula (II):
• A comprises or consists of moiety A1 or A2 as defined herein;
• Y' is wherein R 1 and R 2 are independently selected from the group consisting of H, -CH 2 OH, - CH 2 CH 2 OH, -CH(CH 3 )OH and -CH 2 OPO(OH) 2 , wherein any one of the alkyl hydrogens can be replaced with a halogen, and wherein R 1 and R 2 are not both H;
• B comprises or consists of Polyethylene Glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG Polyethylene Glycol
• the compound comprises moiety A1 , wherein: each g is independently 10, 11, 12, 13, 14, 15, 16, 17 or 18; z is 1 ;
• X is S
• R 6 and R 7 are H
• R 9 and R 10 are both a single bond.
• moiety A1 is defined by moiety A1' wherein each g is independently 10, 11 , 12, 13, 14, 15, 16, 17 or 18.
• any of the compounds described herein may be a compound comprising a moiety A selected from A1' and A2 as defined herein and PEG, wherein the moiety A and PEG are linked by a glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue.
• the compound may comprise or consist of partial structure A1Y' or A2Y':
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl;
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2;
• R 11 , R 12 , R X , R y , R 14 , R 15 , R 16 , and R 17 at each instance of b, v, w, and z are each independently H or C 1 -C 6 aliphatic;
• R, R 13 and R 18 are each independently H or C 1 -C 6 aliphatic;
• L 1 and L2 are each independentlyC 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C 2 -C 20 heteroaliphatic
• A2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , and L 3 is optionally substituted; and A1Y' or A2Y' is covalently linked to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG polyethylene glycol
• the moiety A and PEG are linked by a serine, homoserine, threonine or phosphoserine residue.
• moiety A and PEG are covalently linked to the glycine, serine, homoserine, threonine, phosphoserine, asparagine or glutamine residue, or an ester of a glutamine residue, through the bond(s) denoted by .
• the compound may be:
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl;
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2; and
• PEG polyethylene glycol
• the compound may be:
• R 1 and R 2 are independently selected from the group consisting of H, -CH 2 OH, - CH 2 CH 2 OH, -CH(CH 3 )OH and -OH 2 OPO(OH) 2 , wherein any one of the alkyl hydrogens can be replaced with a halogen, and wherein R 1 and R 2 are not both H;
• PEG polyethylene glycol
• the compound may be:
• R 6 and R 7 are H;
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl;
• R 9 and R 10 are both a single bond; z is 1 ; and X is S; covalently linked to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG polyethylene glycol
• the PEG is covalently linked through the bond denoted by .
• the compound may be:
• R 1 and R 2 are independently selected from the group consisting of H, -CH 2 OH, - CH 2 CH 2 OH, -CH(CH 3 )OH and -OH 2 OPO(OH) 2 , wherein any one of the alkyl hydrogens can be replaced with a halogen, and wherein R 1 and R 2 are not both H; R 6 and R 7 are H;
• R 9 and R 10 are both a single bond; z is 1 ;
• X is S; covalently linked to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG polyethylene glycol
• the PEG is covalently linked through the bond denoted by
• the compound may be:
• R 1 , R 2 and g are as defined herein, salt, solvate or prodrug thereof
• the PEG is covalently linked through the bond denoted by
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl; b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; and the sum of b and w is from 0 to 7; z is 1 or 2;
• R 11 , R 12 , R X , R y , R 14 , R 15 , R 16 , and R 17 at each instance of b, v, w, and z are each independently H or C 1 -C 6 aliphatic;
• R, R 13 and R 18 are each independently H or C 1 -C 6 aliphatic;
• L 1 and L 2 are each independentlyC 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C 2 -C 20 heteroaliphatic
• a 2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , and L 3 is optionally substituted; covalently linked to polyethylene glycol (PEG), or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• PEG polyethylene glycol
• the PEG is covalently linked through the bond denoted by
• the compound may be a compound of formula (III):
• AY comprises or consists of a moiety selected from AY1 and AY2 wherein each of R 1 , R 2 , R 6 , R 7 , R 9 , R 10 , z, X, g, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 ,
• R x , R y , L 1 , L 2 , Z 1 , Z 2 , b, v and w are as defined for the compound of formula (I); and B comprises or consists of Polyethylene Glycol (PEG).
• PEG Polyethylene Glycol
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound is a compound of formula (IV) or (V) wherein R 6 and R 7 are H; R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl;
• R 9 and R 10 are both a single bond; z is 1 ; and X is S.
• the compound of any one of formulas (l)-(V) may be a compound of formula (VI):
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• R 5 is the side chain, or second hydrogen of the amino acid; b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; and the sum of b and w is from 0 to 7; z is 1 or 2;
• R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 at each instance of b, v, w, and z are each independently H or C 1 -C 6 aliphatic;
• R, R 13 and R 18 are each independently H or C 1 -C 6 aliphatic;
• L 1 and L 2 are each independently C 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C 2 -C 20 heteroaliphatic
• a 2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R x , R y , L 1 , L 2 , and L 3 is optionally substituted; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (VIII):
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl;
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (IX):
• A1 is represented by moiety A1 as defined for formula (I)
• Y is wherein R 1 and R 2 are independently selected from the group consisting of H, -CH 2 OH, - CH 2 CH 2 OH, -CH(CH 3 )OH and -CH 2 OPO(OH) 2 , wherein any one of the alkyl hydrogens can be replaced with a halogen, and wherein R 1 and R 2 are not both H;
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound is a compound of formula (VIII) or (IX), wherein R 6 and R 7 are H;
• R 9 and R 10 are both a single bond; z is 1 ;
• the compound may be a compound of formula (X): Pam2Cys-Y-NH-(CH 2 ) p -O-(CH 2 -CH 2 -O) n -[(CH 2 ) m -CO-L-] q R 3
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (XI):
• Pam2Cys has the structure:
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (XII):
• Pam2Cys has the structure:
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (XIII):
• Pam2Cys-Ser has the structure:
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• R 9 and R 10 are independently selected from the group consisting of -NH-, -O- or a single bond; z is 1 or 2;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound has the formula (XV):
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid; b and w are each independently an integer from 0 to 7 and v is an integer from 0 to 5, provided that: the sum of b, v, and w is at least 3; and the sum of b and w is from 0 to 7; z is 1 or 2;
• R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , and R 17 at each instance of b, v, w, and z are each independently H or C 1 -C 6 aliphatic;
• R, R 13 and R 1 s are each independently H or C 1 -C 6 aliphatic;
• L 1 and L 2 are each independently C 5 -C 21 aliphatic or C 4 -C 20 heteroaliphatic;
• L 3 is C 1 -C 21 aliphatic or C2-C 20 heteroaliphatic;
• a 2 is an amino acid or a peptide; wherein any aliphatic or heteroaliphatic present in any of R, R 11 , R 12 , R x , R y , R 14 , R 15 , R 16 , R 17 , R 18 , R 1 9, R x , R y , L 1 , L 2 , and L 3 is optionally substituted; or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• R 6 and R 7 are H
• R 8 is selected from the group consisting of H and a straight or branched C 1 -C 6 alkyl
• R 9 and R 10 are both a single bond; z is ;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (XVIII): wherein n is 3 to 100; k is 3 to 100; m is 1 , 2, 3 or 4; each g is independently 10, 11 , 12, 13, 14, 15, 16, 17 or 18; p is 2, 3 or 4; t is 2, 3 or 4; h is 1 , 2, 3 or 4; q is null or 1 ; wherein R 1 and R 2 are independently selected from the group consisting of H, -CH 2 OH, - CH 2 CH 2 OH, -CH(CH 3 )OH and -CH 2 OPO(OH) 2 , wherein any one of the alkyl hydrogens can be replaced with a halogen, and wherein R 1 and R 2 are not both H; R 6 and R 7 are H;
• R 9 and R 10 are both a single bond; z is 1 ;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H; and R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• the compound may be a compound of formula (XIX):
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
• any compound disclosed herein including a compound of any one of formulas (l)-(XIX)) that comprises polyethylene glycol (PEG) may comprise the PEG in the form of a substituted PEG.
• the substituted PEG is represented by partial formula B-l: wherein n is 3 to 100; m is 1 , 2, 3 or 4; p is 2, 3 or 4; q is null or 1 ;
• R 3 is H, -NH 2 or -OH, wherein when q is null, R 3 is H and when q is 1 , R 3 is -NH 2 or -OH;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid.
• the substituted PEG is represented by partial formula B-ll: wherein p is 2, 3 or 4; n is 3 to 100; m is 1 , 2, 3 or 4; t is 2, 3 or 4; k is 3 to 100; h is 1 , 2, 3 or 4; q is null or 1 ; wherein when q is 1 , R 3 is -NH 2 or -OH; wherein when q is null, R 3 is H;
• L is null or consists of 1 to 10 units, wherein each unit is a natural alpha amino acid or derived from a natural alpha amino acid, and has the formula: wherein R 4 is H;
• R 5 is the side chain, or second hydrogen of the amino acid.
• q is 1 . In some embodiments of the substituted PEG of formula B-l or B-ll, n may be from 10 to
• m is from 1 to 3, such as 2.
• R 3 is -NH 2 .
• L is a natural alpha amino acid residue.
• a composition may comprise a compound in an enantiomerically or diastereomerically enriched form.
• the compound may have an enantiomeric excess (ee) or a diastereomeric excess (de) of at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99%.
• the compound may be enriched by at least about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than
• the compound may comprise a chiral centre around the following chiral centre (shown at *): wherein the chiral centre is in the R configuration.
• a compound in this form may also be referred to as an R-Pam2 analogue diastereomer of a compound of the invention as described herein. This may be depicted as:
• the compound may comprise a chiral centre in the 2,3- bis(palmitoyloxy)propyl moiety of Pam2Cys (shown at *): wherein the chiral centre is in the R configuration.
• a compound in this form may also be referred to as an R-Pam2 diastereomer of a compound of the invention as described herein. This may be depicted as:
• the compound may comprise a chiral centre around the following chiral centre (shown at *): wherein the chiral centre is in the S configuration.
• a compound in this form may also be referred to as an S-Pam2 analogue diastereomer of a compound of the invention as described herein. This may be depicted as:
• the compound comprises a chiral centre in the 2,3-bis(palmitoyloxy)propyl moiety of Pam2Cys (shown at *): wherein the chiral centre is in the S configuration.
• a compound in this form may also be referred to as an S-Pam2 diastereomer of a compound of the invention as described herein. This may be depicted as:
• the compound comprises a chiral centre around the following chiral centre (shown at *): wherein the chiral centre is in the L configuration.
• a compound in this form may also be referred to as an L-Cys analogue diastereomer of Pam2Cys of a compound of the invention as described herein. This may be depicted as:
• the compound comprises a chiral centre in the cysteine residue of Pam2Cys (shown at *): wherein the chiral centre is in the L configuration.
• a compound in this form may also be referred to as an L-Cys diastereomer of Pam2Cys of a compound of the invention as described herein. This may be depicted as:
• stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• the compound comprises a chiral centre in moiety A1 around the following chiral centre (shown at *): wherein the chiral centre is in the D configuration.
• a compound in this form may also be referred to as an D-Cys analogue diastereomer of Pam2Cys of a compound described herein. This may be depicted as:
• stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• the compound comprises a chiral centre in the cysteine residue of Pam2Cys (shown at *): wherein the chiral centre is in the D configuration.
• a compound in this form may also be referred to as an D-Cys diastereomer of Pam2Cys of a compound described herein. This may be depicted as:
• stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• a compound of the present invention may be provided in a chiral form enriched at a chiral centre at the following carbon atom (shown at *) of moiety A2: wherein the chiral centre is in the R configuration.
• this stereoisomer of the compound may be depicted as:
• R 16 , R 17 , R 18 , R 19 , b, v and z are as defined for the compound of Formula (I) and w is 1 .
• Other stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• a compound of the present invention may be provided in a chiral form enriched at a chiral centre at the following carbon atom (shown at *) of moiety A2: wherein the chiral centre is in the S configuration.
• moiety A of this stereoisomer of the compound may be depicted as:
• R 16 , R 17 , R 18 , R 19 , b, v, w, and z are as defined for the compound or Formula (I).
• Other stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• a compound of the present invention may be provided in a chiral form enriched at a chiral centre at the following carbon atom (shown at **) of moiety A2: wherein the chiral centre is in the L configuration.
• a compound in this form may also be referred to as an L-Cys analogue stereoisomer of a compound of the invention. In some embodiments, this stereoisomer of the compound may be depicted as:
• R 16 , R 17 , R 18 , R 19 , b, v, w, and z are as defined for the compound or Formula (I).
• Other stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• a compound of the present invention may be provided in a chiral form enriched at a chiral centre at the following carbon atom (shown at **) of moiety A2: wherein the chiral centre is in the D configuration.
• a compound in this form may also be referred to as a D-Cys analogue stereoisomer of a compound of the invention.
• moiety A of this stereoisomer of the compound may be depicted as:
• L 1 , L 2 , Z 1 , Z 2 , R x , R y , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , b, v and z are as defined for the compound or Formula (I) and w is 1.
• Other stereocentres in these compounds may be racemic or independently enriched in either the R or S configuration.
• the compound comprises a chiral centre in the Y moiety of the compound
• a compound in this form may also be referred to as an L-Y diastereomer of a compound described herein.
• the compound comprises a chiral centre in the Y moiety of the compound
• compositions comprising a compound of the invention (including a compound of any one of formulas (l)-(XIX)) or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient may be used in a method or use of the invention.
• the compound as described herein is the R diastereomer around the chiral centre of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.
• the compound as described herein is the S diastereomer around the chiral centre of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.
• composition as described herein comprises a compound that is the R diastereomer around the chiral centre of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.
• a composition comprises a compound that is the S diastereomer around the chiral centre of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in a composition is the R diastereomer around the chiral centre of the 2,3-bis(palmitoyloxy)propyl moiety of the compound.
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in a composition is the S diastereomer around the chiral centre of the 2,3-bis(palmitoyloxy)propyl moiety of the compound (for example moiety A1).
• the compound as described herein is the L diastereomer around the chiral centre of the cysteine analogue residue of the Pam2Cys analogue moiety compound (for example moiety Y).
• the compound as described herein is the L diastereomer around the chiral centre of the cysteine residue of the Pam2Cys moiety compound (for example moiety Y).
• the compound as described herein is the D diastereomer around the chiral centre of the cysteine analogue residue of the Pam2Cys analogue moiety compound (for example moiety Y).
• the compound as described herein is the D diastereomer around the chiral centre of the cysteine residue of the Pam2Cys moiety of the compound (for example moiety Y).
• a composition as described herein comprises a compound that is the L diastereomer around the chiral centre of the cysteine analogue residue of the Pam2Cys analogue moiety of the compound (for example moiety Y). In any aspect, a composition as described herein comprises a compound that is the L diastereomer around the chiral centre of the cysteine residue of the Pam2Cys moiety of the compound (for example moiety Y).
• composition as described herein comprises a compound that is the D diastereomer around the chiral centre of the cysteine analogue residue of the Pam2Cys analogue moiety of the compound (for example moiety Y).
• composition as described herein comprises a compound that is the D diastereomer around the chiral centre of the cysteine residue of the Pam2Cys moiety of the compound (for example moiety Y).
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the L diastereomer around the chiral centre of the cysteine analogue residue of the Pam2Cys analogue moiety of the compound.
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the L diastereomer around the chiral centre of the cysteine residue of the Pam2Cys moiety of the compound.
• 99% or more than 99% of the compound present in the composition is the D diastereomer around the chiral centre of the cysteine analogue residue of the Pam2Cys analogue moiety of the compound.
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the D diastereomer around the chiral centre of the cysteine residue of the Pam2Cys moiety of the compound.
• the compound of the invention as described herein is the L diastereomer around the chiral centre of the Y moiety.
• the compound as described herein is the D diastereomer around the chiral centre of the Y moiety.
• a composition as described herein comprises a compound that is the L diastereomer around the chiral centre of the Y moiety. In any aspect, a composition as described herein comprises a compound that is the D diastereomer around the chiral centre of the Y moiety.
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the L diastereomer around the chiral centre of the Y moiety.
• 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or more than 99% of the compound present in the composition is the D diastereomer around the chiral centre of the Y moiety.
• the compounds of formulas (l)-(XIX) described herein may demonstrate substantial stability in solution. This solution stability may be observed by storing solutions of the compounds under ambient storage conditions (eg at 25°C) or under accelerated degradation stability (eg at 40°C) for at least about 14 days.
• any of the compounds described herein may be administered in the form of a pharmaceutically acceptable salt.
• pharmaceutically acceptable may be used to describe any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of the invention as described herein, or a pharmaceutically acceptable salt, prodrug or ester thereof, or an active metabolite or residue thereof.
• Suitable pharmaceutically acceptable salts may include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
• pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric,
• Base salts may include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
• pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.
• inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
• polymorph includes any crystalline form of compounds of the invention as described herein, such as anhydrous forms, hydrous forms, solvate forms and mixed solvate forms.
• solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of the invention described herein, or a pharmaceutically acceptable salt, prodrug or ester thereof) and a solvent.
• solvents for the purpose of the invention may not interfere with the biological activity of the solute.
• suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
• the solvent used is a pharmaceutically acceptable solvent.
• suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water.
• Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• lower alkyl halide such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl and diethyl sulfate; and others.
• the compounds as described herein are to also include isotope variations, such as the replacement of hydrogen for deuterium.
• a “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound of the invention as described herein.
• a prodrug may be an acylated derivative of a compound as provided herein.
• Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
• prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
• Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
• Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (eg, two, three or four) amino acid residues which are covalently joined to free amino, and amido groups of any of compounds of Formulas (l)-(XIX).
• the amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvlin, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone.
• Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of the compounds described herein, including the compounds of formulas (l)-(XIX), or other structure as depicted herein.
• aliphatic is intended to include saturated and unsaturated, nonaromatic, straight chain, branched, acyclic, and cyclic hydrocarbons.
• aliphatic groups include, for example, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl and (cycloalkyl)alkenyl groups.
• aliphatic groups comprise from 1 -12, 1-8, 1 -6, or 1-4 carbon atoms.
• aliphatic groups comprise 5-21 , from 9-21 , or from 11-21 carbon atoms, such as from 11 , 13, 15, 17, or 19 carbon atoms.
• the aliphatic group is saturated.
• heteroaliphatic is intended to include aliphatic groups, wherein one or more chain and/or ring carbon atoms are independently replaced with a heteroatom, preferably a heteroatom selected from oxygen, nitrogen and sulfur. In some embodiments, the heteroaliphatic is saturated. Examples of heteroaliphatic groups include linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups.
• alkyl is intended to include saturated straight chain and branched chain hydrocarbon groups.
• alkyl groups have from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or from 1 to 4 carbon atoms.
• alkyl groups have from 5-21 , from 9-21 , or from 11 -21 carbon atoms, such as from 11 , 13, 15, 17, or 19 carbon atoms.
• straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl.
• branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.
• alkenyl is intended to include straight and branched chain alkyl groups having at least one double bond between two carbon atoms.
• alkenyl groups have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms.
• alkenyl groups have from 5-21 , from 9-21 , or from 11 -21 carbon atoms, such as from 11 , 13, 15, 17, or 19 carbon atoms.
• alkenyl groups have one, two, or three carbon-carbon double bonds.
• alkynyl is intended to include straight and branched chain alkyl groups having at least one triple bond between two carbon atoms.
• the alkynyl group have from 2 to 12, from 2 to 10, from 2 to 8, from 2 to 6, or from 2 to 4 carbon atoms.
• heteroalkyl is intended to include alkyl groups, wherein one or more chain carbon atoms are replaced with a heteroatom, preferably a heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroalkyl is saturated. Heteroalkyl groups include, for example, polyethylene glycol groups and polyethylene glycol ether groups, and the like.
• cycloalkyl is intended to include mono-, bi- or tricyclic alkyl groups.
• cycloalkyl groups have from 3 to 12, from 3 to 10, from 3 to 8, from 3 to 6, from 3 to 5 carbon atoms in the ring(s).
• cycloalkyl groups have 5 or 6 ring carbon atoms.
• monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• the cycloalkyl group has from 3 to 8, from 3 to 7, from 3 to 6, from 4 to 6, from 3 to 5, or from 4 to 5 ring carbon atoms.
• Bi- and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bi- and tricyclic ring cycloalkyl systems include, but are not limited to, bicyclo[2.1 1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.
• cycloalkenyl is intended to include non-aromatic cycloalkyl groups having at least one double bond between two carbon atoms. In some embodiments, cycloalkenyl groups have one, two or three double bonds. In some embodiments, cycloalkenyl groups have from 4 to 14, from 5 to 14, from 5 to 10, from 5 to 8, or from 5 to 6 carbon atoms in the ring(s). In some embodiments, cycloalkenyl groups have 5, 6, 7, or 8 ring carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl.
• aryl is intended to include cyclic aromatic hydrocarbon groups that do not contain any ring heteroatoms.
• Aryl groups include monocyclic, bicyclic and tricyclic ring systems. Examples of aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl. In some embodiments, aryl groups have from 6 to 14, from 6 to 12, or from 6 to 10 carbon atoms in the ring(s). In some embodiments, the aryl groups are phenyl or naphthyl.
• Aryl groups include aromatic-aliphatic fused ring systems. Examples include, but are not limited to, indanyl and tetrahydronaphthyl.
• heterocyclyl is intended to include non-aromatic ring systems containing 3 or more ring atoms, of which one or more is a heteroatom.
• the heteroatom is nitrogen, oxygen, or sulfur.
• the heterocyclyl group contains one, two, three, or four heteroatoms.
• heterocyclyl groups include mono-, bi- and tricyclic rings having from 3 to 16, from 3 to 14, from 3 to 12, from 3 to 10, from 3 to 8, or from 3 to 6 ring atoms.
• Heterocyclyl groups include partially unsaturated and saturated ring systems, for example, imidazolinyl and imidazolidinyl.
• Heterocyclyl groups include fused and bridged ring systems containing a heteroatom, for example, quinuclidyl.
• Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, isoxazolidinyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolidinyl, and trithianyl.
• heteroaryl is intended to include aromatic ring systems containing 5 or more ring atoms, of which, one or more is a heteroatom.
• the heteroatom is nitrogen, oxygen, or sulfur.
• heteroaryl groups include mono-, bi- and tricyclic ring systems having from 5 to 16, from 5 to 14, from 5 to 12, from 5 to 10, from 5 to 8, or from 5 to 6 ring atoms.
• Heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, isoxazolopyridinylxanthinyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxaliny
• halo or halogen is intended to include F, Cl, Br, and I.
• heteroatom is intended to include oxygen, nitrogen, sulfur, or phosphorus. In some embodiments, the heteroatom is selected from the group consisting of oxygen, nitrogen, and sulfur.
• substituted is intended to mean that one or more hydrogen atoms in the group indicated is replaced with one or more independently selected suitable substituents, provided that the normal valency of each atom to which the substituent(s) are attached is not exceeded, and that the substitution results in a stable compound.
• optional substituents in the compounds described herein include but are not limited to halo, CN, NO 2 , OH, NH 2 , NHR 100 , NR 100 R 200 , C 1-6 haloalkyl, C 1-6 haloalkoxy, C(O)NH 2 , C(O)NHR 100 , C(O) NR 100 R 200 , SO 2 R 100 , OR 100 , SR 100 , S(O)R 100 , C(O)R 100 , and C 1-6 aliphatic; wherein R 100 and R 200 are each independently C 1-6 aliphatic, for example Ci-ealkyl.
• protecting group PG
• a person skilled in the art would readily understand what type of protecting group would be suitable.
• amine protecting group as used herein is intended to mean a group that is capable of being readily removed to provide the NH 2 group of an amine group and protects the amine group against undesirable reaction during synthetic procedures.
• Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro- Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504.
• Examples include, but are not limited to, acyl and acyloxy groups, for example acetyl, chloroacetyl, trichloroacetyl, 0- nitrophenylacetyl, o-nitrophenoxy-acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyl, aminocaproyl, benzoyl, methoxy-carbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2- trifluoroethoxycarbonyl, 2-trimethylsilylethoxy-carbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichloro-benzyloxycarbonyl, and the like.
• acyl and acyloxy groups for example acetyl, chloroacetyl, trichloroacetyl, 0-
• amine protecting groups for the purposes described herein include (but are not limited to) tert-butyloxycarbonyl (t-Boc) and 9H-fluoren-9-ylmethoxycarbonyl (Fmoc).
• carboxyl protecting group as used herein is intended to mean a group that is capable of being readily removed to provide the OH group of a carboxyl group and protects the carboxyl group against undesirable reaction during synthetic procedures.
• Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro- Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504.
• Examples include, but are not limited to, alkyl and silyl groups, for example methyl, ethyl, fert-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl, and the like.
• carboxamide protecting group as used herein is intended to mean a group that is capable of being readily removed to provide the NH 2 group of a carboxamide group and protects the carboxamide group against undesirable reaction during synthetic procedures.
• protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504.
• Examples include, but are not limited to, 9-xanthenyl (Xan), trityl (Trt), methyltrityl (Mtt), cyclopropyldimethylcarbinyl (Cpd), and dimethylcyclopropylmethyl (Dmcp).
• Xan 9-xanthenyl
• Trt trityl
• Mtt methyltrityl
• Cpd cyclopropyldimethylcarbinyl
• Dmcp dimethylcyclopropylmethyl
• esters refers to a carboxylic acid group where the hydrogen of the hydroxyl group has been replaced by a saturated, straight-chain (i.e. linear) or branched hydrocarbon group.
• alkyl groups are methyl, ethyl, propyl, /so-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso- pentyl, n-hexyl and 2,2-dimethylbutyl.
• the alkyl group may be a C 1 -C 6 alkyl group.
• a wording defining the limits of a range of length such as, for example, "from 1 to 5" means any integer from 1 to 5, i.e. 1 , 2, 3, 4 and 5.
• any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
• the alkyl group may be a branched alkyl group.
• Ser refers to the amino acid serine and ‘Cys’ refers to the amino acid cysteine.
• PEG refers to the polymer compound polyethylene glycol. Unless otherwise defined, reference to ‘PEG’ includes any length polymer of ethylene oxide. Reference to PEG also includes substituted PEG. In some embodiments, substituted PEG may be defined by formulas B-l or B-ll as described herein.
• a therapeutically effective amount of any compound described herein is administered to the subject.
• Administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art including those described herein.
• Pharmaceutical compositions may be formulated from compounds of the invention as described herein for any appropriate route of administration.
• a pharmaceutical composition comprises a pharmaceutically acceptable excipient, carrier and/or diluent. Examples of suitable components for inclusion in a pharmaceutical composition are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences.
• Suitable routes of administration for implementing the defined methods include oral, intravenous, respiratory including inhalation and intranasal (e.g. in order to administer to the respiratory tract, particularly the lower respiratory tract, in particular the lung), intramuscular, topical, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
• parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation.
• Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
• composition described herein may be formulated for administration to the respiratory tract, in other words via a respiratory route. Where administration to all or part of the respiratory tract is contemplated, a skilled person will understand that this includes administration intranasal ly or via inhalation.
• the composition as described herein may be formulated for intranasal administration, including dry powder, sprays, mists, or aerosols.
• Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
• the composition may be a dry powder and administered to the respiratory tract only as defined herein.
• the compound can be formulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension, for intranasal administration as drops or as a spray.
• a solution e.g., water or isotonic saline, buffered or unbuffered, or as a suspension
• such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0.
• Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers.
• a representative nasal decongestant is described as being buffered to a pH of about 6.2 (Remington's, Id. at page 1445).
• a suitable saline content and pH for an innocuous aqueous carrier for nasal and/or respiratory administration is described as being buffered to a pH of about 6.2 (Remington's, Id. at page 1445).
• the ordinary artisan can readily determine a suitable saline content and pH for an innocuous aqueous carrier for nasal and/or respiratory administration.
• ingredients such as art known preservatives, colorants, lubricating or viscous mineral or vegetable oils, perfumes, natural or synthetic plant extracts such as aromatic oils, and humectants and viscosity enhancers such as, e.g., glycerol, can also be included to provide additional viscosity, moisture retention and a pleasant texture and odour for the formulation.
• various devices are available in the art for the generation of drops, droplets and sprays.
• a compound or composition described herein can be administered into the nasal passages by means of a simple dropper (or pipet) that includes a glass, plastic or metal dispensing tube from which the contents are expelled drop by drop by means of air pressure provided by a manually powered pump, e.g., a flexible rubber bulb, attached to one end.
• a simple dropper or pipet
• a manually powered pump e.g., a flexible rubber bulb
• a suitable pharmaceutically acceptable ophthalmic solution can be readily provided by the ordinary artisan as a carrier for the compound or composition described herein to be delivered and can be administered to the orbit of the eye in the form of eye drops to provide for both ophthalmic and intranasal administration.
• a premeasured unit dosage dispenser that includes a dropper or spray device containing a solution or suspension for delivery as drops or as a spray is prepared containing one or more doses of the drug to be administered.
• the invention also includes a kit containing one or more unit dehydrated doses of compound, together with any required salts and/or buffer agents, preservatives, colorants and the like, ready for preparation of a solution or suspension by the addition of a suitable amount of water.
• the water may be sterile or nonsterile, although sterile water is generally preferred.
• therapeutically effective amount or ‘effective amount’ generally refers to an amount of any compound described herein, a pharmaceutically acceptable salt, polymorph or prodrug thereof of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
• Undesirable effects e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "effective amount”.
• a therapeutically effective amount of the compounds or compositions described herein can inhibit tumour growth by at least about 10%, by at least about 20%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 80%, or by at least about 90% or more, relative to untreated subjects.
• the treatments described herein may cause complete regression of the tumour mass.
• tumour regression can be observed and continue for a period of at least about 10 days, at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days or at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days or longer.
• a therapeutically effective amount of a drug may also include a “preventative” or “prophylactically effective amount,” which is any amount of any compound described herein administered to a subject at risk of developing a cancer (eg a subject having a pre-malignant condition) or of suffering a recurrence of cancer, that inhibits the development or recurrence of the cancer.
• the prophylactically effective amount prevents the development or recurrence of the cancer entirely. “Inhibiting” or “preventing” the development or recurrence of a cancer means either lessening the likelihood of the cancer's development or recurrence, or preventing the development or recurrence of the cancer entirely.
• the exact amount of the therapeutically effective amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact therapeutically effective amount. However, an appropriate therapeutically effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
• the dose administered to a subject is any therapeutically effective amount that reduces symptoms associated with the cancer as a result of any one of a reduction in the number of cancer cells; a reduction in the tumour size; an inhibition (i.e., slow to some extent and preferably stop) of cancer cell infiltration into peripheral organs; an inhibition (i.e., slow to some extent and preferably stop) of tumour metastasis; an inhibition, to some extent, of tumour growth; or relieving, to some extent, of one or more of the symptoms associated with the cancer.
• the therapeutically effective amount may lead to increased survival of the subject.
• a therapeutically effective amount of any compound described herein for a human subject lies in the range of about 250 nmoles/kg body weight/dose to 0.005 nmoles/kg body weight/dose.
• the range is about 250 nmoles/kg body weight/dose to 0.05 nmoles/kg body weight/dose.
• the body weight/dose range is about 250 nmoles/kg, to 0.1 nmoles/kg, about 50 nmoles/kg to 0.1 nmoles/kg, about 5 nmoles/kg to 0.1 nmol/kg, about 2.5 nmoles/kg to 0.25 nmoles/kg, or about 0.5 nmoles/kg to 0.1 nmoles/kg body weight/dose.
• the amount is at, or about, 250 nmoles, 50 nmoles, 5 nmoles, 2.5 nmoles, 0.5 nmoles, 0.25 nmoles, 0.1 nmoles or 0.05nmoles/kg body weight/dose of the compound. Dosage regimes are adjusted to suit the exigencies of the situation and may be adjusted to produce the optimum therapeutic dose.
• a therapeutically effective dosage is formulated to contain a concentration (by weight) of at least about 0.1% up to about 50% or more, and all combinations and sub- combinations of ranges therein.
• the compositions can be formulated to contain one or more compounds, or a pharmaceutically acceptable salt, polymorph or prodrug thereof in a concentration of from about 0.1 to less than about 50%, for example, about 49, 48, 47, 46, 45, 44, 43, 42, 41 or 40%, with concentrations of from greater than about 0.1%, for example, about 0.2, 0.3, 0.4 or 0.5%, to less than about 40%, for example, about 39, 38, 37, 36, 35, 34, 33, 32, 31 or 30%.
• compositions may contain from about 0.5% to less than about 30%, for example, about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21 or 20%, with concentrations of from greater than about 0.5%, for example, about 0.6, 0.7, 0.8, 0.9 or 1%, to less than about 20%, for example, about 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10%.
• the compositions can contain from greater than about 1% for example, about 2%, to less than about 10%, for example about 9 or 8%, including concentrations of greater than about 2%, for example, about 3 or 4%, to less than about 8%, for example, about 7 or 6%.
• the active agent can, for example, be present in a concentration of about 5%. In all cases, amounts may be adjusted to compensate for differences in amounts of active ingredients actually delivered to the treated cells or tissue.
• treatment with any compound described herein is continued for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months, at least about 24 months, at least about 3 years, at least about 5 years, or at least about 10 years.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination i.e. other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy.
• treatment or “treating” of a subject includes the application or administration of a compound of the invention to a subject with the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
• treating refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.
• minimising or preventing the progression of cancer means treating the subject so as to prevent or delay the recurrence or metastasis of a tumour, or to prevent growth of an existing tumour.
• Minimising or preventing the progression of cancer includes preventing or delaying the recurrence of cancer, or preventing growth of an existing tumour, following treatment of cancer.
• the recurrence that is being prevented includes a recurrence for example, in the tumour bed, following surgical excision.
• recurrence includes metastasis of the cancer in another part of the body.
• the terms “preventing recurrence” and “preventing relapse” as used herein, are interchangeable.
• the present invention also includes methods of preventing the development of cancer in an individual.
• the individual for whom prevention of cancer is required may be considered to be at risk of developing cancer, but does not yet have detectable cancer.
• An individual at risk of the development of cancer may be an individual with a family history of cancer, and/or an individual for whom genetic testing or other testing indicates a high risk or high likelihood of the development of cancer.
• the individual may have cancer stem cells but does not yet have any detectable tumours. It will be understood that methods of preventing the development of cancer include methods of delaying the onset of cancer in a subject.
• the terms “subject”, “individual” and “patient” will be understood to be interchangeable. Although the invention finds application in humans, the invention is also useful for therapeutic veterinary purposes. The invention is useful for domestic or farm animals such as cattle, sheep, horses and poultry; for companion animals such as cats and dogs; and for zoo animals.
• cancer will be understood to include benign, pre-cancerous, pre-neoplastic or non-metastatic tumours or metastatic tumours.
• the type of cancer to be treated includes those having a benign, pre-cancerous, pre-neoplastic or non-metastatic tumour.
• a benign tumour will be understood to not be a malignant tumour and to not invade nearby tissue or spread to other parts of the body.
• non-metastatic cancer will be understood to not invade nearby tissue or spread to other parts of the body.
• Pre-cancerous or pre-neoplasia generally refers to a condition or a growth that typically precedes or develops into a cancer.
• a "pre-cancerous" growth may have cells that are characterized by abnormal cell cycle regulation, proliferation, or differentiation, which can be determined by markers of cell cycle.
• the cancer is a secondary cancer or metastases.
• the secondary cancer may be located in any organ or tissue, and particularly those organs or tissues having relatively higher hemodynamic pressures, such as lung, liver, kidney, pancreas, bowel and brain.
• the secondary cancer may be detected in the ascites fluid and/or lymph nodes.
• identifying a subject having cancer there is a step of identifying a subject having cancer. This may include the identification of a pre-cancerous or pre-neoplastic growth, secondary cancer or metastasis.
• Pre-neoplastic, neoplastic and metastatic cancers are particular examples to which the methods of the invention may be applied.
• Broad examples include breast tumours, colorectal tumours, adenocarcinomas, mesothelioma, bladder tumours, prostate tumours, germ cell tumour, hepatoma/cholongio, carcinoma, neuroendocrine tumours, pituitary neoplasm, small round cell tumour, squamous cell cancer, melanoma, atypical fibroxanthoma, seminomas, nonseminomas, stromal leydig cell tumours, Sertoli cell tumours, skin tumours, kidney tumours, testicular tumours, brain tumours, ovarian tumours, stomach tumours, oral tumours, bladder tumours, bone tumours, cervical tumours, esophageal tumours, laryngeal tumours, liver tumours, lung tumours, vaginal tumours and Wilm's tumour.
• cancers include but are not limited to adenocarcinoma, adenoma, adenofibroma, adenolymphoma, adontoma, AIDS related cancers, acoustic neuroma, acute lymphocytic leukemia, acute myeloid leukemia, adenocystic carcinoma, adrenocortical cancer, agnogenic myeloid metaplasia, alopecia, alveolar soft-part sarcoma, ameloblastoma, angiokeratoma, angiolymphoid hyperplasia with eosinophilia, angioma sclerosing, angiomatosis, apudoma, anal cancer, angiosarcoma, aplastic anaemia, astrocytoma, ataxia-telangiectasia, basal cell carcinoma (skin), bladder cancer, bone cancers, bowel cancer, brain stem glioma, brain and
• B-cell mixed cell, null-cell, T-cell, T-cell chronic, HTLV-llassociated, lymphangiosarcoma, lymphocytic acute, lymphocytic chronic, mast- cell and myeloid), leukosarcoma, leydig cell tumour, liposarcoma, leiomyoma, leiomyosarcoma, lymphangioma, lymphangiocytoma, lymphagioma, lymphagiomyoma, lymphangiosarcoma, male breast cancer, malignant- rhabdoid-tumour-of-kidney, medulloblastoma, melanoma, Merkel cell cancer, mesothelioma, metastatic cancer, mouth cancer, multiple endocrine neoplasia, mycosis fungoides, myelodysplastic syndromes, myeloma, myeloproliferative disorders, malignant carcinoid syndrome carcinoid heart disease, medulloblastoma
• ocular cancers oesophageal cancer, oral cavity cancer, oropharynx cancer, osteosarcoma, ostomy ovarian cancer, pancreas cancer, paranasal cancer, parathyroid cancer, parotid gland cancer, penile cancer, peripheral- neuroectodermal-tumours, pituitary cancer, polycythemia vera, prostate cancer, osteoma, osteosarcoma, ovarian carcinoma, papilloma, paraganglioma, paraganglioma nonchromaffin, pinealoma, plasmacytoma, protooncogene, rare-cancers-and- associated- disorders, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, Rothmund- Thomson syndrome, reticuloendotheliosis, rhabdomyoma, salivary gland cancer, sarcoma, schwannoma, S
• a condition or symptom associated with the cancer may be any pathology that arises as a consequence of, preceding, or proceeding from the cancer.
• the condition or relevant symptom may be microbial infection.
• the condition or symptom may relate to organ dysfunction of the relevant organ having tumour metastases.
• the methods of treatment described herein are for the prevention of progression or treatment of a condition or symptom in an individual that is associated with a cancer in the individual.
• a positive response to treatment or a minimisation of progression of a cancer may be determined by any method known in the art and may include the determination of:
• tumour size a reduction in the tumour size
• inhibition i.e., slow to some extent and preferably stop
• tumour metastasis an inhibition (i.e., slow to some extent and preferably stop) of tumour metastasis
• a negative response or a lack of response of a cancer to a treatment including any compound described herein may be determined by any method known in the art and may include the determination of: no change or an increase in the number of cancer cells;
• the subject who has received the treatment for cancer may be in partial or complete remission.
• the subject, having received a treatment for cancer, as described above may have a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater reduction in the measurable parameters of tumour growth as may be found on physical examination, radiologic study, or by biomarker levels from a blood or urine test.
• the subject may have substantially undetectable signs of cancer.
• a cancer that is “substantially undetectable” generally refers to a circumstance where therapy has depleted the size, volume or other physical measure of a cancer so that using relevant standard detection techniques such as in vivo imaging, the cancer, as a consequence of the therapy, is not clearly detectable.
• the objective or outcome of treatment with any compound described herein may be to reduce the number of cancer cells; reduce the primary tumour size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumour metastasis; inhibit, to some extent, tumour growth; and/or relieve to some extent one or more of the symptoms associated with the disorder.
• Efficacy of treatment can be measured by assessing the duration of survival, time to disease progression, the response rates (RR), duration of response, and/or quality of life.
• the method is particularly useful for delaying cancer progression. In one embodiment, the method is particularly useful for extending survival of the subject, including overall survival as well as progression free survival. It will be understood that overall survival is the length of time from either the date of diagnosis or the start of treatment of a cancer, that patients diagnosed with the cancer are still alive. It will be understood that progression free survival is the length of time during and after the treatment of a cancer that a patient lives with the disease but it does not get worse.
• the Kaplan-Meier method estimates the survival function from life-time data. In medical research, it can be used to measure the fraction of patients living for a certain amount of time after treatment.
• a plot of the Kaplan-Meier method of the survival function is a series of horizontal steps of declining magnitude which, when a large enough sample is taken, approaches the true survival function for that population. The value of the survival function between successive distinct sampled observations ("clicks") is assumed to be constant.
• Kaplan-Meier curve An important advantage of the Kaplan-Meier curve is that the method can take into account "censored" data- losses from the sample before the final outcome is observed (for instance, if a patient withdraws from a study). On the plot, small vertical tick-marks indicate losses, where patient data has been censored. When no truncation or censoring occurs, the Kaplan- Meier curve is equivalent to the empirical distribution.
• the method is particularly useful for providing a complete response to therapy whereby all signs of cancer in response to treatment have disappeared. This does not always mean the cancer has been cured. In one embodiment, the method is particularly useful for providing a partial response to therapy whereby there has been a decrease in the size of one or more tumours or lesions, or in the extent of cancer in the body, in response to treatment. Kits
• kit or article of manufacture comprising any compound described herein, a pharmaceutically acceptable salt, diluent or excipient and/or pharmaceutical composition as described above. Further, the kit may comprise instructions for use in any method or use of the invention as described herein.
• kits for use in a therapeutic and/or prophylactic application mentioned above comprising:
• kit may contain one or more further active principles or ingredients for treatment of cancer.
• the therapeutic composition of the kit is formulated for administration to the respiratory tract, preferably by inhalation.
• the kit or “article of manufacture” may comprise a container and a label or package insert on or associated with the container.
• Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.
• the containers may be formed from a variety of materials such as glass or plastic.
• the container holds a therapeutic composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle).
• the label or package insert indicates that the therapeutic composition is used for treating the condition of choice.
• the label or package insert includes instructions for use and indicates that the therapeutic or prophylactic composition can be used to treat a cancer described herein.
• the kit may comprise (a) a therapeutic or prophylactic composition; and (b) a second container with a second active principle or ingredient contained therein.
• the kit in this embodiment of the invention may further comprise a package insert indicating the composition and other active principle can be used to treat a cancer or prevent progression of a cancer described herein.
• Compounds of the invention may be prepared by techniques known in the art.
• compounds of the invention including any one of formulas (l)-(XIX) comprising an A1 moiety may be prepared by techniques described in WO2019/119067, the entire contents of which are hereby incorporated by reference.
• Compounds of the invention including any one of formulas (l)-(XIX) comprising an A2 moiety may be provided by coupling a compound of the formula A2-I:
• B' is a Polyethylene Glycol (PEG); and is a solid support resin.
• B' comprises a substituted PEG of Formula B-l.
• the following sequence of solid phase reactions may be employed: a) Optionally coupling 1 to 10 alpha amino acids or compounds derived from a natural alpha amino acid, that constitutes L, to a solid phase resin using Fmoc chemistry b) Coupling PG-NH-(CH 2 ) p -O-(CH 2 CH 2 O) n -(CH 2 ) m -COOH to a solid phase resin or substituted resin if L is present, wherein PG represents an amino protecting group compatible with Fmoc chemistry; c) Removing PG; d) Coupling PG-NH-CR 13 R 14 -COOH, wherein PG' represents an amino protecting group compatible with Fmoc chemistry; e) Removing PG'; f) Coupling an acid of the formula (A-l); g) Optionally removing R 19 and optionally acylating and/or alkyl
• B’ comprises a substituted PEG according to formula (B-ll) and the following sequence of solid phase reactions may be employed: a) Optionally coupling 1 to 10 alpha amino acids or compounds derived from a natural alpha amino acid, that constitute L, to a solid phase resin using Fmoc chemistry b) Coupling PG-NH-(CH 2 ) t -O-(CH 2 CH 2 O) k -(CH 2 ) h -COOH to a solid phase resin or substituted resin if L is present, wherein PG represents an amino protecting group compatible with Fmoc chemistry; c) Removing PG; d) Coupling PG'-NH-(CH 2 ) p -O-(CH 2 CH 2 O) n -(CH 2 ) m -COOH, wherein PG' represents an amino protecting group compatible with Fmoc chemistry; e) Removing PG’; f) Coupling PG”-NH-CR 13 R
• the compound of formula A2-I is provided in the form of a compound of formula A2-II: wherein L 1 , L 2 , X, v, w and R 18 are as defined for the compound of formula A-l above, Z 1 and Z 2 are independently selected from -NHC(O)-, -C(O)NH-, -OC(O)-, -C(O)O-, -NHC(O)O- and -OC(O)O-.
• the compound of formula A2-II may be prepared by the synthesis shown in Scheme 1.
• Scheme 1 describes the synthesis of embodiments of the compound of formula A2-II, wherein X is S,
• L 1 -Z 1 are -OC(O)E-(CH 2 ) g -CH 3 , wherein E is -O- or -NH- and g is 10, 11 , 12, 13, 14, 15, 16, 17 or 18;
• L 2 -Z 2 are -OC(O)E-(CH 2 ) g -CH 3 , wherein E is -O- or -NH- and g is 10, 11 , 12, 13, 14, 15, 16, 17 or 18; and R 19 is PG3, which is an amino protecting group.
• PG is a suitable protecting group, for example a silyl group such as TBDMS
• the epoxide formation maybe carried out to give the product racemically or to give enantioenriched material. If a racemic or scalemic mixture of enantiomers is produced preparative chiral chromatography is employed to separate the enantiomers if required.
• Epoxides of the formula (VI') are reacted with suitably protected cystine analogues, for example tert- butyl N -(((9H-fluoren-9-yl)methoxy)carbonyl)-S-(((R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)thio)-D-cysteinate, where PG2 is a tert- butyl ester and PG3 is Fmoc, under reducing conditions to give alcohols of the formula (VII').
• cystine analogues for example tert- butyl N -(((9H-fluoren-9-yl)methoxy)carbonyl)-S-((R)-2-((((9H-fluoren-9- yl)methoxy)carbonyl)amino)-3-(tert-
• alcohols of the formula (VII') can be comprised of more than one stereoisomer and where stereoisomers are present these can be separated by chiral preparative chromatography as required.
• Alcohols of the formula (VII') can be acylated to give carbonyl containing adducts of the formula (VIII') using suitable reagents. Where esters are required, acid chlorides can be reacted in the presence of suitable bases and solvents; where carbamates are required isocyanates can be reacted in the presence of suitable bases and solvents and where carbonates are required chloroformates can be reacted in the presence of suitable bases and solvents.
• Carbonyl containing adducts of the formula (VIII') can then be deprotected to reveal carboxylic acids of the formula (IX') using suitable reagents, for example where PG2 is tert-butyl, trifluoroacetic acid can be used to preferentially remove the tert-butyl group.
• Acids of the formula (IX') can then be used as reagents in solid phase synthesis to add groups of formula Y and B.
• B’ is a Polyethylene Glycol (PEG);
• PG s is H or a sulphur protecting group, such as tert-butyl; and is a solid support resin. Following optional sulphur deprotection, this resin bound peptide may be reacted with a 1 ,2-epoxy-alkanol of the following formula: wherein R x , R y and v have the meanings given for moiety A2, for example as defined in formula (I) to provide an alkylated thiol of formula S-1 : wherein Y' and B' have the meaning given above, and v has the meaning given for moiety A2, or a sulfone or sulfoxide thereof.
• the diol moieties of resin bound compound S-1 may be further reacted to provide a compound of the invention, for example, by diol functionalisation with palmitic groups or lauryl carbamate groups, etc.
• Example 1 Effect of synthetic compound A101/compound 1 on tumour growth, survival and metastasis.
• compound A101 referred to in the Examples and Figures as Compound 1).
• mice C57BL/6 or Balb/c Wild-type (WT) mice were purchased from Walter and Eliza Hall Institute for Medical Research or bred in house and maintained at the QIMR Berghofer Medical Research Institute. Mice greater than 8 weeks of age were sex-matched to the appropriate models. The number of mice in each group treatment or strain of mice for each experiment is indicated in the figure legends. In all studies, no mice were excluded based on pre-established criteria and randomization was applied immediately prior to treatment in therapy experiments. Experiments were conducted as approved by the QIMR Berghofer Medical Research Institute Animal Ethics Committee.
• Mouse B16F10 (melanoma), MC38 (colon adenocarcinoma) and 4T1.2 (breast cancer) cells were grown in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% Fetal Calf Serum (Bovogen), 1% Glutamine (Gibco), and 1% Penicillin/Streptomycin (Gibco).
• DMEM Dulbecco's Modified Eagle Medium
• Bovogen Fetal Calf Serum
• Glutamine Gibco
• Penicillin/Streptomycin Gibco
• B16F10 and 4T1.2 cells were maintained at 37°C, 5% CO2.
• MC38 cells were maintained at 37°C, 10% CO2. All cell lines were routinely tested negative for Mycoplasma, but cell line authentication was not routinely performed.
• mice For primary tumour growth experiments MC38 (1 x 10 6 ) or B16F10 (1 x 10 5 ) cells were subcutaneous (s.c.) injected into mice in a final volume of 100 ml (day 0). Treatment of mice commenced as indicated in figures or legends. Digital callipers were used to measure the perpendicular diameters of each individual tumour. The tumour size was calculated and is presented as mean ⁇ SEM. When tumours reached a size of 150 mm 2 mice were sacrificed.
• 5x 10 4 4T1.2 cells were injected into the 4th mammary fat pad in a volume of 50 ml (day 0).
• day 12 after injection primary tumours were surgically removed under isoflurane anaesthesia.
• Mice were injected treated as indicated in figure legends on day 15, 18 and 21 after tumour cell injection. All mice were sacrificed on day 26 after tumour cell injection for evaluation of metastatic burden. For this, macroscopic visible lung metastases were counted.
• mice C57BL/6 WT mice were s.c injected with highly immunogenic MC38 colon carcinoma cells. Once tumours were palpable ( ⁇ 5 mm in diameter), mice were randomized into three groups receiving three intratumoral injections of vehicle, 25 mg or 50 mg compound 1 in 100 mI saline (Figure 1A). A dose dependent inhibition of MC38 tumour growth was observed along with significantly improved overall survival of mice treated with compound 1 compared to vehicle control ( Figure 1B, C).
• Example 2 Compound A108 has anti-tumour activity in the MC38 model.
• Compound A108 slows tumour growth during the treatment phase via the i.t ( Figure 6A) or i.p ( Figure 6B) routes. Lastly, the effect of compound A108 was superior to the effect of Pam3CysSK4 (Figure 6C), and at least as comparable as the effect of commercially available anti-PD1 antibodies ( Figure 6D).
• Example 3 Compound A108 has anti-tumour activity in the WEHI164 model.
• mice were subcutaneously inoculated with the WEHI164 tumour cell-line and established tumours were monitored by calliper measurement. When tumours reached 30mm 2 the mice were treated either via the i.v or i.p route with a single dose of compound A108 or PBS (Figure 7A). All mice were monitored for tumour growth ( Figure 7B, D).
• mice were dosed with a single injection of the indicated doses per mouse.
• a group was injected intraperitoneally (i.p.) to test whether this route of administration could provide a quicker and safer means of drug delivery, while providing a similar therapeutic outcome.
• the i.p. treated group produced a better rate of survival that the i.v route ( Figure 7C, E).
• tumours were measured 48 hours after start of treatment, they had already responded, which is very quick for immunotherapy. Tumour regression was marked by a discolouration (blackening) of the tumour within 24 hours post treatment, exhibiting a scab on the surface in the middle, with only a small rind of tumour left, if at all (data not shown).
• Example 4 Compound A108 significantly impairs spontaneous lung metastasis in mice bearina EMT6.5 tumours.
• RTQ- PCR real time quantitative PCR
• Example 5 Intranasal administration of compound A108 reduces lung metastasis in mice bearing 4T1.2 tumours.
• Compound A108 was next used to test its efficacy upon intranasal administration. For this, we orthotopically injected mice with highly metastatic 4T1.2 breast cancer cells into the 4 th mammary fat pad. Once tumours reached ( ⁇ 7-8 mm in diameter), mice were subjected to surgery and the primary tumour was removed. Subsequently mice were randomized into groups receiving three intranasal administrations of either vehicle or 2.5 ng compound A108 in 50 mI saline in experiment 1 ( Figure 9A) or 0.25 ng compound A108 in 50 mI saline in experiment 2 ( Figure 9B). Two weeks after surgery all mice were sacrificed and the number of visible lung metastases were counted. In both independently performed experiments, intranasal administration of compound A108 significantly reduced the number of 4T1.2 breast cancer metastases in the lung ( Figure 9C).
• Example 6 Various compounds significantly improve the survival and reduce tumour growth in MC38-bearina mice.
• C57BL/6 WT mice were s.c injected with highly immunogenic MC38 colon carcinoma cells. Once tumours were palpable ( ⁇ 5 mm in diameter), mice were randomized into two groups receiving intratumoral injections of vehicle or 25 mg of the indicated compound A102 or A103 in 100 mI saline.
• Example 7 Representative synthesis and characterisation of selected compounds of the invention: A107. A108. A115. A116. A117. A118. A203. A204. A215. A216. A220 and
• Fmoc S-2,3-di(palmitoloxypropyl)-cysteine S-Fmoc-Dpc-OH_ was purchased from Bachem Inc.
• Fmoc-Dpc-OH (100mg, 0.24 mmol) is activated in DCM and DMF (1 :1 , v/v, 3mL ) with FIOBt (36 mg, 0.24 mmol) and N,N'- diisopropylcarbodiimide (DICI; 37 uL, 0.24 mmol) at 0 °C for 5 min.
• the solution is removed by filtration on a glass sinter funnel (porosity 3) and the resin washed with DCM and DMF (3 x 30mL each). The reaction is monitored for completion using the trinitrobenezene sulfonic acid (TNBSA) test. If necessary a double coupling is performed.
• TBSA trinitrobenezene sulfonic acid
• reaction mixture was held at 50 °C for 2hrs in a water bath and then the solid support then thoroughly washed with DMF.
• sulfone or sulfoxide derivatives may be prepared by oxidation of the corresponding sulfide (eg A115) with an oxidant such as meta- chloroperoxybenzoic acid (MCPBA) or tert- butyl hydroperoxide (t-BuOOH) under appropriate conditions.
• MCPBA meta- chloroperoxybenzoic acid
• t-BuOOH tert- butyl hydroperoxide
• Fmoc-Ser(tBu)-OH is then coupled to provide intermediate A2, followed by the coupling of Boc-Cys(StBu) A1 .
• the thiol-tert-butyl group on the cysteine residue was removed by incubating the peptide resin in 0.5M of dithiothreitol for 1 hr in DMF at RT.
• Palmitic acid (320mg, 1.25 mmol), DIPCDI (225 uL, 1.5mmol) and 4- dimethylaminopyridine (DMAP; 15.25mg, 0.125mmol) were dissolved in 2mL of dichloromethane (DCM) then added to the resin-bound BOC-Dhc-peptide resin A3 (0.0625 mmol, 0.25 g) and shaken for 16h at room temperature. The supernatant was removed by filtration and the solid support thoroughly washed with DCM and dimethylformamide (DMF) to remove any residue of urea before being subjected to the cleavage process as described below.
• DCM dichloromethane
• DMF dimethylformamide
• the solid support bearing the assembled lipopeptide was exposed to reagent B (93% TFA, 5% water and 2% triisopropylsilane) for 2 hours. To isolate the product, most of the TFA was removed and the residue is then dissolved in 50% acetonitrile and purified immediately using the purification protocol described below or the material was freeze-dried and stored for later purification.
• A220 was synthesized by standard Fmoc Solid Phase Peptide Synthesis, starting with Fmoc-RINK MBPIA PS Resin. Removal of the Fmoc group after each coupling was achieved using 20% piperidine in DMF.
• the first recoupling was done using Myristyl Chloroformate (12 eq. vs. moles resin), NMM (24 eq. vs. moles resin) in dry DCM/TFIF (85/15) for 18 hours at room temperature.
• the second recoupling was done using Myristyl Chloroformate (6 eq. vs. moles resin), NMM (12 eq. vs. moles resin) in dry DCM/THF (85/15) for 41 hours at room temperature.
• A224 Compound A224 was synthesized by standard Fmoc Solid Phase Peptide Synthesis, starting with Chlorotrityl Chloride Resin with an initial substitution of 1 .6 meq/g.
• the first amino acid, Fmoc-Gly-OH was loaded on the resin first, using a 0.5-fold molar excess of Fmoc-Gly-OH and DIEA (1.5-fold excess), followed by capping with DMF/MeOH/DIEA (80/10/10), and Fmoc deprotection, to obtain the dry loaded H-Gly-CT Resin with a final substitution of 0.67 meq/g. Removal of the Fmoc group after each coupling was achieved using 20% Piperidine in DMF.
• Protocol A Reversed phase HPLC was conducted using an Agilent Zorbax 300SB-C3, 5um column (9.4 mm ⁇ 250 mm; Agilent Technology, Australia) installed in an Agilent HPLC 1260 Infinity system (Agilent Technologies, Santa Clara, California, USA) with the chromatogram developed using Buffer A (0.1% trifluoroacetic acid in water) and buffer B (0.1% trifluoroacetic acid in acetonitrile).
• Protocol B Reverse phase chromatography was conducted using a Novasep Axial Compression Column (5-cm diameter) loaded with cyano media (Daisogel SP-120-CN-P), with a gradient of Acetonitrile in [0.1%TFA/Water]. Following intermediate lyophilization, ion-exchange was performed on Dowex ion-exchange resin in order to obtain the peptide as the acetate salt.
• HPLC column Agilent Zorbax 300-SB C3 (150 x 0.5 mm; 5mm) with the following gradient conditions: 0-5min, 20%B: 5-32min, 20%B-100%B: 32-40min, 100%B-20%B. The flow rate was 20 mI/min.
• LC-MS Agilent 1100 series capillary LC system in-line with an Agilent 1100 series LC/MSD ion-trap mass spectrometer. The mass spectrometer was operated with electrospray ionisation configured in the positive ion mode. Data analysis software from Agilent Technologies was used to de-convolute the charged ion series for identification of the peptide material and the material then characterised by LC-MS.
• Quantitation of compounds A107, A108, A115, A116, A203, A204, A215 and A216 was carried out by in vacuo hydrolysis at 110°C of samples in sealed glass vials in the presence of 6N HCI containing 0.1% phenol. Derivatisation of amino acids was then carried out using Waters AccQTag reagents according to the manufacturer's instructions followed by analysis on a Waters Acquity UPLC System (Waters Millipore) using an AccQTag ultra column (2.1mm x 100mm; Waters Millipore). Quantitation of other compounds may be achieved by a similar protocol.
• Sulfone and sulfoxide derivatives of compounds A215 and A216 may be accessed by a similar synthetic routes as described above, with the omission of ethylmethylsulfide scavenger, and optional omission of nitrogen sparging, from the carbamate formation step.
• This reaction may yield a mixture of thiol, sulfone and sulfoxide derivatives, which may be separated and purified by HPLC.
• sulfone or sulfoxide derivatives may be prepared by oxidation of the corresponding sulfide with an oxidant such as meta-chloroperoxybenzoic acid (MCPBA) or tert- butyl hydroperoxide (t-BuOOH) under appropriate conditions.
• MCPBA meta-chloroperoxybenzoic acid
• t-BuOOH tert- butyl hydroperoxide

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