AU2022392831A1 - Cytarabine-amino acid based prodrug for the treatment of cancer - Google Patents
Cytarabine-amino acid based prodrug for the treatment of cancer Download PDFInfo
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- AU2022392831A1 AU2022392831A1 AU2022392831A AU2022392831A AU2022392831A1 AU 2022392831 A1 AU2022392831 A1 AU 2022392831A1 AU 2022392831 A AU2022392831 A AU 2022392831A AU 2022392831 A AU2022392831 A AU 2022392831A AU 2022392831 A1 AU2022392831 A1 AU 2022392831A1
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Classifications
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- 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
- A61K47/54—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 compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/09—Pyrimidine radicals with arabinosyl as the saccharide radical
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
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- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to conjugates comprising amino-acid-cytarabine, in particular, conjugates of cytarabine and two or more amino acids selected from alanine, aspartic acid, glutamic acid, asparagine, or glutamine for use in the treatment of cancer.
Description
CYTARABINE- AMINO ACID BASED PRODRUG FOR THE TREATMENT OF
CANCER
FIELD OF THE INVENTION
[001] The present invention relates to active prodrugs of conjugates comprising cytarabine and at least two amino acids selected from alanine, aspartic acid, glutamic acid, asparagine, or glutamine substituted on both of the sugar and the cytosine moieties of the drug for use in the treatment of cancer. In particular, the present invention relates to prodrug conjugates of cytarabine, aspartic acid and/or additional amino acid for use in the treatment of cancer or a pre-cancer condition or disorder.
BACKGROUND OF THE INVENTION
Anti-Proliferative Drugs
[002] Anti-proliferative drugs, also known as anti-metabolites, anti-neoplastic agents or covalent DNA binding drugs, act by inhibiting essential metabolic pathways and are commonly used in the treatment of malignant diseases. However, their high toxicity to normal cells and severe side effects limits their use as therapeutic agents. Undesirable side effects include anemia, emesis and balding due to cytotoxic effects on rapidly dividing normal cells, such as stem cells in the bone marrow, epithelial cells of the intestinal tract, hair follicle cells, etc.
Nucleotide/Nucleoside analogs
[003] A significant proportion of current chemotherapeutic treatments for cancer involve the use of anti-metabolites, particularly modified nucleoside analogues that possess a capability to mimic native purine or pyrimidine nucleosides which can disrupt metabolic and regulatory pathways. Nucleoside analogs compete with their physiologic counterparts for incorporation into nucleic acids and have earned an important place in the treatment of leukemia. These molecules can be taken up by nucleoside transporters and then phosphorylate to their mono-, di- and triphosphate forms where they are able to interfere with DNA/RNA synthesis and repair; for example, by acting as chain terminators or ribonucleotide reductase inhibitors. Other notable modes of action include epigenetic regulation, through inhibition of DNA regulatory proteins, such as DNA methyltransferase._Selected current examples of anticancer nucleoside analogues approved for
chemotherapeutic treatment regimens include capecitabine, gemcitabine, clofarabine and cytarabine (Ara-C). The latter compound belongs to the arabinose nucleosides; a unique class of antimetabolites originally isolated from the sponge Cryptothethya crypta, but now produced synthetically. They differ from the physiologic deoxyribonucleosides by the presence of a 2’ -OH group in the cis configuration relative to the N-glycosyl bond between cytosine and arabinoside sugar. Several arabinose nucleosides have useful antitumor and antiviral effects. The most active cytotoxic agent of this class is cytosine arabinoside Ara-C. Cytarabine (Ara-C) is one of the most effective drugs for treating cancers of white blood cells such as Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), and Myelodysplastic Syndromes (MDS). However, cytarabine is highly toxic having severe side-effects such as cerebellar toxicity and bone marrow suppression. Intermediate and high dose cytarabine treatment is therefore limited, and often restricted, in elderly patients and unfit patients.
[004] One objective of analog development in the area of cytidine antimetabolites has been to find compounds that preserve the biological activity of Ara-C but do not undergo rapid deamination and deactivation. A number of deaminase-resistant analogs have been developed, including cyclo-cytidine (Ho DHW, 1974) and N4-behenoyl Ara-C (Kodama et al., 1989) that showed anti-leukemic activity in some clinical trials, but had undesirable side effects (Woodcock et al., 1980). Other representative compounds are N4- Palmitoyl- Ara-C, 2’ -Azido -2’ -deoxy Ara- C, 5’-(Cortisone 21 -phosphoryl) ester of Ara-C, 5’-Acyl esters of Ara-C (e.g., 5’-palmitate ester), N4 Behenoyl-ara-C, Ara-C conjugate with poly-H5 (2-hydroxyethyl)-L-glutamine, Dihydro-5- azacytidine, 5-Aza-arabinosylcytosine, 5 -Aza-2’ -deoxy cytidine and 2’ -2 ’-Difluorodeoxy cytidine (Hartel et al., 1990 and Heineman et al., 1988).
[005] N-amino acid derivatives of cytarabine such as Aspartic acid (Asp)-(Cytarabine) also known as N4-aspartyl-cytarabine or Glutamic acid (Glu)-(Cytarabine) or N4-glutamyl-cytarabine are deaminase-resistant analogs due to blockage of the cytarabine-amine by the side chain of the amino acid that creates a stable amide bound (U.S patents 7,989,188 and 8,993,278).
Cytarabine metabolism
[006] Once a nucleotide-based drug such as cytarabine (Ara-C) is transported within the cell, it requires activation for its cytotoxic effect. The first metabolic step is the conversion of cytarabine to cytarabine-monophosphate (Ara-CMP) by deoxycytidine kinase. Ara-CMP is subsequently phosphorylated to diphosphate (Ara-CDP) and triphosphate (Ara-CTP) by pyridine monophosphate kinase and pyridine diphosphate kinase, respectively. Ara-CTP is the active
metabolite of Ara-C it competes with the native substrate deoxycytidine triphosphate (dCTP) for DNA incorporation by DNA polymerase. After incorporation, it functions as DNA chain terminator interfering with chain elongation and repair. Ara-C cytotoxicity is most effective in the S phase of cell cycle, during period of rapid DNA synthesis (Book: Cancer, Principles & Practice of Oncology, Lippincott, Williams and Wilkins, 7th Edition, 2000).
[007] Catabolism of Ara-C involves two key enzymes, cytidine deaminase and deoxycytidine deaminase that convert Ara-C and Ara-CMP to inactive metabolites Ara-U and Ara-UMP, respectively.
Pro-drugs and Proliferative Disease
[008] The use of prodrugs to impart desired characteristics such as increased bioavailability or increased site- specificity is a recognized concept in the art of pharmaceutical development. For example, direct or indirect conjugation of a drug to an antibody creates a stable conjugate that can arrive at the target site with minimum dissociation of the drug. Drug targeting may be combined with a mechanism of selective release of the drug for maximal potency.
[009] U.S. Patent No. 4,296,105 describes doxorubicin derivatives linked to an optionally substituted amino acid at the hydroxy group of the amino acid residue, which possess in vitro a higher antitumor activity and lower toxicity than doxorubicin.
[0010] U.S. Patent No. 5,962,216 teaches tumor activated prodrugs which are unable to enter the cell until cleaved by a factor or factors secreted by a target cell.
[0011] U.S. Patent No. 5,650,386 teaches compositions comprising at least one active agent, and at least one modified non-alpha amino acid or poly amino acid, which acts as a carrier of the active agent. The amino acid modification includes acylation or sulfonation of at least one free amine group.
[0012] U.S. Patent Nos. 6,623,731; 6,428,780 and 6,344,213 teach non-covalent mixtures comprising modified amino acids as carriers for biologically active agents
[0013] U.S. Patent No. 5,106,951 discloses a conjugate comprising an aromatic drug non- covalently intercalated between two aromatic side chains on an oligopeptide, and an antibody or antibody fragment covalently attached to the oligopeptide for targeting to cancer cells.
[0014] U.S. Patent No. 6,617,306 teaches a carrier for the in vivo delivery of a therapeutic agent, the carrier and therapeutic agent linked by a disulfide bond. According to U.S. Patent No. 6,617,306, the carrier comprises a polymer, and at least one thiol compound conjugated to the
polymer, such that the thiol group of the thiol compound and the thiol group of the therapeutic agent form a disulfide bond.
[0015] International Patent Application Publication No. WO 00/33888 teaches cleavable antitumor and anti-inflammatory compounds comprising a therapeutic agent capable of entering a target cell, an oligopeptide, a stabilizing group and an optional linker.
[0016] International Patent Application Publication No. 2005/072061 and U.S. Patent Nos. 7,989,188 and 8,993,278 disclose compounds comprising a drug covalently linked to a functional group of an amino acid side chain, such compounds are useful for targeting drugs to neoplastic cells.
[0017] Manfredini et al., (2000) discloses the synthesis of peptide T- Ara-C conjugates for targeting CD4 positive cells.
[0018] There remains an unmet need for methods of treating cancer which comprise administering to cancer patients’ compounds having antitumor activity but reduced cytotoxicity to normal tissues.
SUMMARY OF THE INVENTION
[0019] In some embodiments this invention provides a conjugate or a pharmaceutically acceptable salt thereof of a cytarabine residue and at least two amino acids, represented by the structure of Formula (A):
isomer thereof, wherein
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine;
R4 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and
wherein at least one of R1, R2, R3 and R5 is an amino acid residue.
[0020] In some embodiments this invention provides a conjugate or a pharmaceutically acceptable salt thereof of a cytarabine residue and at least two amino acids, represented by the structure of Formula (B):
isomer thereof, wherein
Asp is an aspartic acid residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not hydrogen (H).
[0021] In some embodiments this invention provides a conjugate or a pharmaceutically acceptable salt thereof of a cytarabine residue and at least two amino acids, represented by the structure of Formula (C):
isomer thereof, wherein
Glu is a glutamic acid residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not hydrogen (H).
[0022] In some embodiments this invention provides a pharmaceutical composition comprising the conjugate described herein and a pharmaceutically acceptable carrier.
[0023] In some embodiments this invention provides a dosage form comprising the composition described herein, wherein the composition is formulated in a dosage form selected from tablets, pills, dragees, lozenges, capsules, powders, liquids, gels, syrups, slurries, suspensions, solutions, emulsions, aerosol spray, sustained-release formulations and the like.
[0024] In some embodiments, this invention provides a method of treating a cancer or a pre- cancerous condition or disorder in a subject in need thereof, comprising administering the pharmaceutical composition described herein. In other embodiments, the cancer is a non-solid tumor or a solid tumor or a combination thereof. In other embodiments, the solid tumor comprises tumors in the central nervous system (CNS), liver cancer, colorectal carcinoma, breast cancer, gastric cancer, pancreatic cancer, bladder carcinoma, cervical carcinoma, head and neck tumors, vulvar cancer, and dermatological neoplasms. In other embodiments, the non-solid tumor comprises leukemias, lymphomas, and multiple myeloma. In other embodiments, the cancer is selected from the group consisting of hematological cancers and non- hematological cancers. In other embodiments, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS).
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows HPLC analysis of Conjugate lb, detected at 247 nm, indicating main peak of the product at 16.6 minutes with 92.8 area% purity.
Figure 2 shows analysis of Cytarabine with two aspartic acid by spectrophotometer, indicating 3 main peaks of the product at 214, 247 and 299 nm.
Figure 3 shows analysis of Conjugate lb by Mass Spectrometer, indicating the molecular mass of the product as 473 g/mol.
Figure 4 shows the effect of Cytarabine with two aspartic acid in-vitro on human and mice leukemia cell growth. Both MOLT-4 and L1210 cell growth is inhibited by Cytarabine with two aspartic acid.
Figure 5 shows the stability of Cytarabine with two aspartic acid in RPMI medium, in relative percentage (%) as compared to its degradation products: aspacytarabine and cytarabine. The main degradation product of Cytarabine with two aspartic acid is aspacytarabine.
Figure 6 shows the stability of Cytarabine with two aspartic acid in RPMI medium with serum, in relative percentage (%) as compared to its degradation products: aspacytarabine (BST-236) and cytarabine.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention provides pharmaceutically acceptable salt forms of conjugates of at least two amino acids covalently linked to therapeutic agents. In particular, the present invention relates to pharmaceutically acceptable salts of conjugates comprising nucleotide drug comprising purine analogue, or anti metabolites drugs and at least two amino acids residue, pharmaceutical compositions comprising these conjugates and use thereof for the treatment of cancer or a precancer condition or disorder.
[0026] In some embodiments, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of a nucleotide drug (D) and at least two amino acids, represented by the structure of Formula (I):
(AA3)y-AAl-D-(AA2)x (I) wherein
D denotes a nucleoside drug, the drug is selected from the group consisting of purine analogue, or anti metabolites;
AA1 is an amino acid residue; wherein AA1 and D are attached via a group selected from amide, ester, ether, thio amide, thio ester, thio ether, urea, amine, ketone, alkyl linker and carbamate;
(AA2)x is an amino acid residue, repeated x times on D, wherein x is 0-10; wherein AA2 and D are attached via a group selected from amide, ester, ether, thio amide, thio ester, thio ether, urea, amine, keton, alkyl linker, and carbamate;
(AA3)y is an amino acid residue, repeated y times on AA1, wherein y is 0-1; wherein AA3 and the AA1 are attached via a group selected from amide, ester, ether, thio amide, thio ester, thio ether, urea, and carbamate; and wherein x+y > 1.
[0027] In another embodiment, said purine analogue is selected from thioguanine, azathioprine, mercaptopurine, clofarabine, pentostatin, cladribine, and fludarabine. In another embodiment, said purine analogue is thioguanine. In another embodiment, said purine analogue is azathioprine. In another embodiment, said purine analogue is mercaptopurine. In another embodiment, said purine analogue is clofarabine. In another embodiment, said purine analogue is pentostatin. In another embodiment, said purine analogue is cladribine. In another embodiment, said purine analogue is fludarabine.
[0028] In another embodiment, said anti metabolite is selected from 5 -fluorouracil, capecitabine, cytarabine, floxuridine, gemcitabine, methotrexate, pemetrexed, and phototrexate. In another embodiment, said anti metabolite is 5 -fluorouracil. In another embodiment, said anti metabolite is capecitabine. In another embodiment, said anti metabolite is cytarabine. In another embodiment, said anti metabolite is floxuridine. In another embodiment, said anti metabolite is gemcitabine. In another embodiment, said anti metabolite is methotrexate. In another embodiment, said anti metabolite is pemetrexed. In another embodiment, said anti metabolite is phototrexate.
[0029] In some embodiments, AA1, AA2 and AA3 of formula (I) are each independently any of D or L, natural or synthetic amino acid residue known in the art. In another embodiment, the amino acid residue of AA1, AA2 and AA3, are each independently selected from the group consisting of Alanine (Ala), aminoisobutyric acid (Aib), arginine (Arg), asparagine (Asn), aspartic acid (Asp), citrulline (Cit), cysteine (Cys), cystine, diaminobutanoic acid, diaminobutyric acid (Dab), diaminopropionic acid (Dpr), dihydroxyphenylalanine, dimethylarginine, glutamic acid (Glu), pyroglutamic acid (p-Glu), glutamine (Gin), histidine (His), 1-methyl-histidine, 3 -methylhistidine, homoserine (Hse), homocitrulline, hydroxyproline (Hyp), lysine (Lys), methyl-lysine, dimethyl lysine, trimethyl lysine, azidolysine, methionine (Met), methionine-sulfoxide, methionine-sulfone, ornithine (Orn), sarcosine (Sar), Selenocystein (Sec), serine (Ser), phosphorserine, methyl-serine, aminoserine (Ams), thienylalanine (Thi), threonine (Thr), phosphothreonine, tryptophan (Trp), tyrosine (Tyr), methyl-tyrosine, phosphor-tyrosine, sulfo-tyrosine, a- aminosuberic acid, 3,5-diiodotyrosine, penicillamine (Pen), 4-ethylamine phenylglycine, 4- aminophenylglycine, 4-sulfophenylalanine, 4-aminophenylalanine and 2-amino-4[4-(2-amino)- pyrimidinyl] butanoic acid, 3 -aminopropionic acid, 6-aminohexanoic acid (s-Ahx), p- aminobenzoic acid, isonipecotic acid, statine (Sta), 2-aminobutyric acid (Abu) and 4-aminobutyric acid, and derivatives and analogs thereof. Each possibility represents a separate embodiment of the present invention.
[0030] In a preferred embodiment, the amino acid residue of AA1, AA2 and AA3, of Formula (I) are each individually selected from a group consisting of Alanine (Ala), asparagine (Asn), aspartic acid (Asp), glutamic acid (Glu), and glutamine (Gin). In another embodiment, the amino acid residue is Ala. In another embodiment, the amino acid residue is Asn. In another embodiment, the amino acid residue is Asp. In another embodiment, the amino acid residue is Glu. In another embodiment, the amino acid residue is Gin.
[0031] In some embodiments, x of Formula (I) is an integer between 0-10. In another embodiment, x is an integer between 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 1-2, 1-3, 1-4, 1-5, 1-6, 1-10. In another embodiment, x is 0. In another embodiment, x is 1. In another embodiment, x is 2. In another embodiment, x is 3. In another embodiment, x is 4. In another embodiment, x is 5. In another embodiment, x is 6. In another embodiment, x is 7. In another embodiment, x is 8. In another embodiment, x is 9. In another embodiment, x is 10.
[0032] In some embodiments, y of Formula (I) is an integer between 0-1. In another embodiment, y is 0. In another embodiment, y is 1.
[0033] In some embodiment, x+y of formula (I) is > 1. In another embodiment, x+y is in the range of l>x+y>2, 1> x+y >3, 1> x+y >5, 1> x+y >7, or 1> x+y >11, Each possibility represents a separate embodiment of the present invention. In another embodiment, X+Y is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, Each possibility represents a separate embodiment of the present invention.
[0034] In some embodiment, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of conjugate (I) - a cytarabine residue and at least two amino acids, represented by the structure of conjugate (A):
wherein
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine;
R4 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is an amino acid residue.
[0035] In another embodiment, the amino acid residue of R1, R2, R3, or R4 of conjugate (A) are each independently linked to the cytarabine through an a-carboxylic acid or a carboxylic acid side chain. In another embodiment, the amino acid residue of R1, R2, R3, or R4 are each independently linked to cytarabine via an amide or an ester, each represent a different embodiment of this invention. In another embodiment, the amino acid residue of R1, R2, R3, or R4 are each independently linked to cytarabine via an amide or an ester group. Each represent a different embodiment of this invention.
[0036] In another embodiment, the amino acid of R5 of conjugate (A) is linked to R4 through an a- amino, a-carboxylic acid or a carboxylic acid side chain. In another embodiment, the amino acid residue of R5 is linked to R4 via an amide group. Each represent a different embodiment of this invention. In another embodiment, the amino acid residue of R5 is linked to R4 via an amide group. Each represent a different embodiment of this invention.
[0037] In some embodiments, the amino acid residue is selected from the group consisting of aspartic acid, glutamic acid, asparagine, glutamine, alanine and derivatives and analogs thereof. Each represent a separate embodiment of this invention. In one currently preferred embodiment, the amino acid residue is aspartic acid. In another currently preferred embodiment, the amino acid residue is glutamic acid.
[0038] In some embodiments, at least two of R1, R2, and R3 of conjugate (A) are different.
[0039] In some embodiments, at least two of R1, R2, and R3 of conjugate (A) are the same.
[0040] In some embodiments, if R1, R2, or R3 of conjugate (A) is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, then the amino acid residue is the same as R4. In another embodiment, R1, R2, R3, R4, or any combination thereof is an aspartic acid. In another embodiment, R1, R2, R3, R4, or any combination thereof are each a glutamic acid. In another embodiment, R1, R2, R3, R4, or any combination thereof are each an asparagine. In another embodiment, R1, R2, R3, R4, or any combination thereof are each a glutamine. In another embodiment, R1, R2, R3, R4, or any combination thereof are each an alanine.
[0041] In some embodiments, if R1, R2, or R3 of conjugate (A) is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, then the amino acid residue is different than R4.
[0042] In some embodiments, R4 and R5 of conjugate (A) are the same amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R4 and R5 are each an aspartic acid. In another embodiment, R4 and R5 are each a glutamic acid. In another embodiment, R4 and R5 are each an asparagine. In another embodiment, R4 and R5 are each a glutamine. In another embodiment, R4 and R5 are each an alanine.
[0043] In some embodiments, R4 and R5 of conjugate (A) are each a different amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. Each represent a separate embodiment of this invention.
[0044] In some embodiments, R1, R2, and R3 of conjugate (A) are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, wherein at least one of R1, R2, or R3 is not H, and R5 is H.
[0045] In some embodiments, R1, R2, and R3 of conjugate (A) are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine.
[0046] In some embodiments, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of conjugate (I) or (A) - a cytarabine residue and at least two amino acids, represented by the structure of conjugate
isomer thereof, wherein
Asp is an aspartic acid residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not H.
[0047] In some embodiments, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of conjugate (I) or (A) - a cytarabine residue and at least two amino acids, represented by the structure of conjugate
isomer thereof, wherein
Glu is a glutamic acid residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not H.
[0048] In some embodiments, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of conjugate (I) or (A) - a cytarabine residue and at least two amino acids, represented by the structure of conjugate
isomer thereof, wherein
Ala is an alanine residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not H.
[0049] In some embodiments, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of conjugate (I) or (A) - a cytarabine residue and at least two amino acids, represented by
R5
NH-Asn the structure of conjugate (
(E), or isomer thereof, wherein
Asn is an asparagine residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not H.
[0050] In some embodiments, provided herein is a conjugate or a pharmaceutically acceptable salt thereof of conjugate (I) or (A) - a cytarabine residue and at least two amino acids, represented by the structure of conjugate
isomer thereof, wherein
Gin is a glutamine residue;
R1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is not H.
[0051] In another embodiment, the amino acid residue of R1, R2, or R3 of conjugates (B)-(F) are each independently linked to the cytarabine through an a-carboxylic acid or a carboxylic acid side chain. In another embodiment, the amino acid residue of R1, R2, or R3 are each independently linked to cytarabine via an ester group. In some embodiments, the Asp of conjugate (B) is linked to the cytarabine through its a-carboxylic acid or a carboxylic acid side chain. In another embodiment, the Asp residue is linked to cytarabine via an amide or an ester group.
[0052] In some embodiments, the Glu of conjugate (C) is linked to the cytarabine through its a- carboxylic acid or a carboxylic acid side chain. In another embodiment, the Glu residue is linked to cytarabine via an amide or an ester group.
[0053] In some embodiments, the Ala of conjugate (D) is linked to the cytarabine through its a- carboxylic acid. In another embodiment, the Ala residue is linked to cytarabine via an amide or an ester group.
[0054] In some embodiments, the Asn of conjugate (E) is linked to the cytarabine through an a- carboxylic acid. In another embodiment, the Asn residue is linked to cytarabine via an amide or an ester group.
[0055] In some embodiments, the Gin of conjugate (F) is linked to the cytarabine through an a- carboxylic acid. In another embodiment, the Gin residue is linked to cytarabine via an amide or an ester group.
[0056] In another embodiment, the amino acid of R5 is linked to Asp of conjugate (B) through an a-amino, a-carboxylic acid or a carboxylic acid side chain. In another embodiment, the amino acid residue of R5 is linked to Asp via an amide group.
[0057] In another embodiment, the amino acid of R5 is linked to Glu of conjugate (C) through an a-amino, a-carboxylic acid or a carboxylic acid side chain. In another embodiment, the amino acid residue of R5 is linked to Glu via an amide group.
[0058] In another embodiment, the amino acid of R5 is linked to Ala of conjugate (D) through an a-amino, a-carboxylic acid. In another embodiment, the amino acid residue of R5 is linked to Ala via an amide group.
[0059] In another embodiment, the amino acid of R5 is linked to Asn of conjugate (E) through an a-amino, a-carboxylic acid. In another embodiment, the amino acid residue of R5 is linked to Asn via an amide group.
[0060] In another embodiment, the amino acid of R5 is linked to Gin of conjugate (F) through an a-amino, a-carboxylic acid. In another embodiment, the amino acid residue of R5 is linked to Gin via an amide group.
[0061] In some embodiments, at least two of R1, R2, and R3 of conjugate (A)-(F) are different.
[0062] In some embodiments, at least two of R1, R2, and R3 of conjugate (A)-(F) are the same.
[0063] In some embodiments, R1, R2, and R3 of conjugates (B)-(F) are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, wherein at least one of R1, R2, or R3 is not H, and R5 is H.
[0064] In some embodiments, R1, R2, and R3 of conjugates (B)-(F) are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine.
[0065] In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an aspartic acid. In some embodiment, at least one of R1, R2, and R3 of conjugates (A)-(F) is a glutamic acid. In some embodiment, at least one of R1, R2, and R3 of conjugates (A)-(F) in an asparagine. In some embodiment, at least one of R1, R2, and R3 of conjugates (A)-(F) is a glutamine. In some embodiment, at least one of R1, R2, and R3 of conjugates (A)-(F) is an alanine.
[0066] In some embodiments, R1 of conjugates (A)-(F) is H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R1 is H. In another embodiment, R1 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R1 is an aspartic acid. In another embodiment, R1 is a glutamic acid. In another embodiment, R1 is an asparagine. In another embodiment, R1 is glutamine. In another embodiment, R1 is an alanine.
[0067] In some embodiments, R2 of conjugates (A)-(F) is H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R2 is H. In another embodiment, R2 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R2 is an aspartic acid. In another embodiment, R2 is a glutamic acid. In another embodiment, R2 is an asparagine. In another embodiment, R2 is glutamine. In another embodiment, R2 is an alanine.
[0068] In some embodiments, R3 of conjugates (A)-(F) is H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R3 is H. In another embodiment, R3 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R3 is an aspartic acid. In another embodiment, R3 is a glutamic acid. In another embodiment, R3 is an asparagine. In another embodiment, R3 is glutamine. In another embodiment, R3 is an alanine.
[0069] In some embodiments, R4 of conjugate (A) is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R4 is an aspartic acid. In another embodiment, R4 is a glutamic acid. In another
embodiment, R4 is an asparagine. In another embodiment, R4 is glutamine. In another embodiment, R4 is an alanine.
[0070] In some embodiments, R5 of conjugates (A)-(F) is H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R5 is H. In another embodiment, R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R5 is an aspartic acid. In another embodiment, R5 is a glutamic acid. In another embodiment, R5 is an asparagine. In another embodiment, R5 is glutamine. In another embodiment, R5 is an alanine.
[0071] In some embodiments, R1, R2, R3 and R5 of conjugates (A)-(F) are each independently H or an aspartic acid residue. In some embodiments, at least one of R1, R2, R3 and R5 of conjugates (A)-(F) is an aspartic acid residue. In another embodiment, R1 is an aspartic acid residue. In another embodiment, R2 is an aspartic acid residue. In another embodiment, R3 is an aspartic acid residue. In another embodiment, R5 is an aspartic acid residue.
[0072] In some embodiments, at least two of R1, R2, R3 and R5 of conjugates (A)-(F) is an aspartic acid residue. In some embodiments, at least three of R1, R2, R3 and R5 of conjugates (A)-(F) is an aspartic acid residue.
[0073] In some embodiments, R1, R2, R3 and R5 of conjugates (A)-(F) are each independently H or a glutamic acid residue. In some embodiments, at least one of R1, R2, R3 and R5 of conjugates (A)-(F) is a glutamic acid residue. In another embodiment, R1 is a glutamic acid residue. In another embodiment, R2 is a glutamic acid residue. In another embodiment, R3 is a glutamic acid residue. In another embodiment, R5 is a glutamic acid residue.
[0074] In some embodiments, at least two of R1, R2, R3 and R5 of conjugates (A)-(F) is a glutamic acid residue. In some embodiments, at least three of R1, R2, R3 and R5 of conjugates (A)-(F) is a glutamic acid residue.
[0075] In some embodiments, R1, R2, R3 and R5 of conjugates (A)-(F) are each independently H or an alanine residue. In some embodiments, at least one of R1, R2, R3 and R5 of conjugates (A)- (F) is an alanine residue. In another embodiment, R1 is an alanine residue. In another embodiment, R2 is an alanine residue. In another embodiment, R3 is an alanine residue. In another embodiment, R5 is an alanine residue.
[0076] In some embodiments, at least two of R1, R2, R3 and R5 of conjugates (A)-(F) is an alanine residue. In some embodiments, at least three of R1, R2, R3 and R5 of conjugates(A)-(F) is an alanine residue.
[0077] In some embodiments, R1, R2, R3 and R5 of conjugates (A)-(F) are each independently H or an asparagine residue. In some embodiments, at least one of R1, R2, R3 and R5 of conjugates (A)-(F) is an asparagine. In another embodiment, R1 is an asparagine residue. In another embodiment, R2 is an asparagine residue. In another embodiment, R3 is an asparagine residue. In another embodiment, R5 is an asparagine residue.
[0078] In some embodiments, at least two of R1, R2, R3 and R5 of conjugates (A)-(F) is an asparagine residue. In some embodiments, at least three of R1, R2, R3 and R5 of conjugates (A)-(F) is an asparagine residue.
[0079] In some embodiments, R1, R2, R3 and R5 of conjugates (A)-(F) are each independently H or a glutamine residue. In some embodiments, at least one of R1, R2, R3 and R5 of conjugates(A)- (F) is a glutamine residue. In another embodiment, R1 is a glutamine residue. In another embodiment, R2 is a glutamine residue. In another embodiment, R3 is a glutamine residue. In another embodiment, R5 is a glutamine residue.
[0080] In some embodiments, at least two of R1, R2, R3 and R5 of conjugates (A)-(F) is a glutamine residue. In some embodiments, at least three of R1, R2, R3 and R5 of conjugates (A)-(F) is a glutamine residue.
[0081] In some embodiments, R1, R2, and R3 of conjugates (A)-(F) are H and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R1, R2, and R3 are H and R5 is an aspartic acid. In another embodiment, R1, R2, and R3 are H and R5 is a glutamic acid. In another embodiment, R1, R2, and R3 are H and R5 is an alanine. In another embodiment, R1, R2, and R3 are H and R5 is an asparagine. In another embodiment, R1, R2, and R3 are H and R5 is a glutamine.
[0082] In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an aspartic acid residue. In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an aspartic acid residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least one of R1, R2, and R3 is an aspartic acid residue and R5 is an aspartic acid. In another embodiment, at least one of R1, R2, and R3 is an aspartic acid residue and R5 is a glutamic acid. In another embodiment, at least one of R1, R2, and R3 is an aspartic acid residue and R5 is an alanine residue. In another embodiment, at least one of R1, R2, and R3 is an aspartic acid residue and R5 is H. In another embodiment, at least one of R1, R2, and R3 is an aspartic acid and R5 is an asparagine residue. In another embodiment, at least one of R1, R2, and R3 is an aspartic acid residue and R5 is a glutamine residue.
[0083] In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are aspartic acid residue. In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are aspartic acid residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least two of R1, R2, and R3 are aspartic acid residue and R5 is an aspartic acid residue. In another embodiment, at least two of R1, R2, and R3 are aspartic acid residue and R5 is a glutamic acid residue. In another embodiment, at least two of R1, R2, and R3 are aspartic acid residue and R5 is an alanine residue. In another embodiment, at least two of R1, R2, and R3 are aspartic acid residue and R5 is an asparagine residue. In another embodiment, at least two of R1, R2, and R3 are aspartic acid residue and R5 is a glutamine residue.
[0084] In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is a glutamic acid residue. In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is a glutamic acid residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least one of R1, R2, and R3 is a glutamic acid residue and R5 is an aspartic acid residue. In another embodiment, at least one of R1, R2, and R3 is a glutamic acid residue and R5 is a glutamic acid residue. In another embodiment, at least one of R1, R2, and R3 is a glutamic acid residue and R5 is an alanine residue. In another embodiment, at least one of R1, R2, and R3 is a glutamic acid residue and R5 is an asparagine residue. In another embodiment, at least one of R1, R2, and R3 is a glutamic acid residue and R5 is a glutamine residue.
[0085] In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are glutamic acid residue. In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are glutamic acid residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least two of R1, R2, and R3 are glutamic acid residue and R5 is an aspartic acid. In another embodiment, at least two of R1, R2, and R3 are glutamic acid and R5 is a glutamic acid residue. In another embodiment, at least two of R1, R2, and R3 are glutamic acid residue and R5 is an alanine residue. In another embodiment, at least two of R1, R2, and R3 are glutamic acid residue and R5 is an asparagine residue. In another embodiment, at least two of R1, R2, and R3 are glutamic acid residue and R5 is a glutamine residue.
[0086] In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an alanine residue. In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an alanine residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic
acid, asparagine, glutamine, and alanine. In another embodiment, at least one of R1, R2, and R3 is an alanine residue and R5 is an aspartic acid residue. In another embodiment, at least one of R1, R2, and R3 is an alanine residue and R5 is a glutamic acid residue. In another embodiment, at least one of R1, R2, and R3 is an alanine residue and R5 is an alanine residue. In another embodiment, at least one of R1, R2, and R3 is an alanine residue and R5 is an asparagine residue. In another embodiment, at least one of R1, R2, and R3 is an alanine residue and R5 is a glutamine residue. [0087] In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are alanine residue. In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are alanine residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least two of R1, R2, and R3 are alanine residue and R5 is an aspartic acid residue. In another embodiment, at least two of R1, R2, and R3 are alanine residue and R5 is a glutamic acid residue. In another embodiment, at least two of R1, R2, and R3 are alanine residue and R5 is an alanine residue. In another embodiment, at least two of R1, R2, and R3 are alanine residue and R5 is an asparagine residue. In another embodiment, at least two of R1, R2, and R3 are alanine residue and R5 is a glutamine residue.
[0088] In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an asparagine residue. In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is an asparagine residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least one of R1, R2, and R3 is an asparagine residue and R5 is an aspartic acid residue. In another embodiment, at least one of R1, R2, and R3 is an asparagine residue and R5 is a glutamic acid residue. In another embodiment, at least one of R1, R2, and R3 is an asparagine residue and R5 is an alanine residue. In another embodiment, at least one of R1, R2, and R3 is an asparagine residue and R5 is an asparagine residue. In another embodiment, at least one of R1, R2, and R3 is an asparagine residue and R5 is a glutamine residue.
[0089] In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are asparagine residue. In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are asparagine residue and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least two of R1, R2, and R3 are asparagine residue and R5 is an aspartic acid residue. In another embodiment, at least two of R1, R2, and R3 are asparagine residue and R5 is a glutamic acid residue. In another embodiment, at least two of R1, R2, and R3 are asparagine residue and R5 is an alanine residue. In another embodiment, at least two of R1, R2, and R3 are asparagine residue and R5 is an asparagine residue.
In another embodiment, at least two of R1, R2, and R3 are asparagine residue and R5 is a glutamine residue.
[0090] In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is a glutamine residue. In some embodiments, at least one of R1, R2, and R3 of conjugates (A)-(F) is a glutamine residue and R5 an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least one of R1, R2, and R3 is a glutamine residue and R5 is an aspartic acid residue. In another embodiment, at least one of R1, R2, and R3 is a glutamine residue and R5 is a glutamic acid residue. In another embodiment, at least one of R1, R2, and R3 is a glutamine residue and R5 is an alanine residue. In another embodiment, at least one of R1, R2, and R3 is a glutamine residue and R5 is an asparagine. In another embodiment, at least one of R1, R2, and R3 is a glutamine residue and R5 a glutamine residue.
[0091] In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are glutamine residue. In some embodiments, at least two of R1, R2, and R3 of conjugates (A)-(F) are glutamine and R5 an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, at least two of R1, R2, and R3 are glutamine residue and R5 is an aspartic acid. In another embodiment, at least two of R1, R2, and R3 are glutamine residue and R5 is a glutamic acid. In another embodiment, at least two of R1, R2, and R3 are glutamine residue and R5 is an alanine residue. In another embodiment, at least two of R1, R2, and R3 are glutamine residue and R5 is an asparagine residue. In another embodiment, at least two of R1, R2, and R3 are glutamine residue and R5 a glutamine residue.
[0092] In another embodiment, R1 is an aspartic acid residue. In another embodiment, R2 is an aspartic acid residue. In another embodiment, R3 is an aspartic acid residue. In another embodiment, R5 is an aspartic acid residue. In some embodiments, at least two of R1, R2, R3 and R5 of conjugates (A)-(F) an aspartic acid residue. In some embodiments, at least three of R1, R2, R3 and R5 of conjugates (A)-(F) an aspartic acid residue.
[0093] In some embodiments, R1, R2, and R3 of conjugates (A)-(F) are H and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. In another embodiment, R1, R2, and R3 are H and R5 is an aspartic acid. In another embodiment, R1, R2, and R3 are H and R5 is a glutamic acid. In another embodiment, R1, R2, and R3 are H and R5 is an alanine. In another embodiment, R1, R2, and R3 are H and R5 is an asparagine. In another embodiment, R1, R2, and R3 are H and R5 is a glutamine.
[0094] In some embodiments, at least two of R1, R2, R3, and R5 of conjugate (A), (B), (C), (D), (E), or (F) are aspartic acid.
[0095] In some embodiments, conjugate (B) of this invention is represented by the following conjugates (Table 1):
[0096] In some embodiments, conjugate (B) of this invention is represented by the structure of the following conjugates Bl and B2:
isomer thereof.
[0097] In some embodiments, conjugate 1 of this invention is represented by the structure of the following conjugates la, lb, 1c, Id or isomer thereof:
[0098] In some embodiments, conjugate 2 of this invention is represented by the structure of the following conjugates 2a, 2b, 2c, 2d or isomer thereof:
[0099] In some embodiments, conjugate 16 of this invention is represented by the structure of the following conjugates 16a, 16b, 16c, 16d or isomer thereof:
[00100] In some embodiments, conjugate 31 of this invention is represented by the structure of the following conjugates 31a, 31b, or isomer thereof:
[00101] In some embodiments, conjugate 4 of this invention is represented by the structure of the following conjugates 4a, 4b, 4c, 4d or isomer thereof:
[00102] In some embodiments, conjugate C of this invention, wherein R1 is glutamic acid is represented by the structure of the following conjugates Cla, Clb, Clc, Cid or isomer thereof:
[00103] In some embodiments, the pharmaceutically acceptable salt of conjugate (I), (A), (B), (C), (D), (E) , (F), and conjugates 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, Cla-Clb and isomer thereof is a salt of an organic or inorganic acid selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, trifluoroacetic acid, methaphosphoric
acid, camphorsulfonic acid, toluenesulfonic acid, PTSA (para-toluenesulfonic acid), benzenesulfonic acid, sulfuric acid, cyclamic acid, di(t-butyl)-naphthalenesulfonic acid, di(t- butyl)-naphthalenedisulfonic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, glycerophosphoric acid, hydrobromic acid, hydroiodic acid, 2-hydroxy- ethanesulfonic (isethionic) acid, medronic (bisphosphonic) acid, methaphosphoric acid, naphthalene- 1,5 -di sulfonic acid, naphthalene-2- sulfonic acid and nitric acid. Each possibility represents a separate embodiment of the present invention.
[00104] In another embodiment, the pharmaceutically acceptable salt of conjugate (I), (A), (B), (C), (D), (E), (F), and conjugates 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, Cla-Clb and isomer thereof is a salt of a strong acid. In another embodiment, the pharmaceutically acceptable salt of conjugate (I), (A), (B), (C), (D), (E), (F), and conjugates 1-218, la-ld, 2a-2d, 31a, 31b, 16a- 16d, 4a-4d, Cla-Clb and isomer thereof is hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt is methanesulfonic acid.
[00105] Without wishing to be bound to a specific name or acronym of the compounds described in this invention, the compounds can be named according to any acceptable name to skilled in the art, for example: (A) Aspartate-Cytarabine-Aspartate (a composition comprising at least one of conjugate selected from 1-4, la-ld, 2a-2d, 4a-4d or isomer thereof) can be named as di-aspartyl- cytarabine, di-aspartate-cytarabine Asp-Ara-C-Asp, di-Asp-Ara-C, Ara-C di-aspartic, Ara-C with two aspartic acid, di-Asp-Cyt, etc.
[00106] Without wishing to be bound to any theory or mechanism of action, the di-amino-acid- cytarabine conjugates can enter into the cells as an intact compound or following degradation overtime to amino-acid-cytarabine conjugates, which are transported into the cancer cells and within the cells these conjugates release cytarabine which arrests cell growth or kill the cell. As free cytarabine and free cytarabine metabolites were detected in cancer cells, the conjugates of the present invention act as pro-drugs.
Pharmaceutical Compositions
[00107] The present invention provides pharmaceutical compositions comprising at least one of the conjugates of the present invention and a pharmaceutically acceptable carrier, solubilizer or diluent, optionally further comprising one or more excipients.
[00108] In some embodiments, provided herein, a pharmaceutical composition comprising at least one conjugate disclosed in this invention or an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the conjugate of this invention or an isomer thereof or a pharmaceutically acceptable salt thereof is
selected from (I), (A)-(F), conjugates 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Clb. Each represent a separate embodiment of this invention. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (A) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (B) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (C) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (D) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (E) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition of this invention comprising conjugate (F) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[00109] In some embodiments, provided herein, a pharmaceutical composition comprising at least one conjugate disclosed in this invention and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least one conjugate selected from the group consisting of (I), (A)-(F), conjugates 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Clb and combination thereof. Each represent a separate embodiment of this invention.
[00110] In another embodiment, provided herein, the pharmaceutical composition comprises two, three or more conjugates selected from the group consisting of (I), (A)-(F), conjugates 1-218, laid, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Clb and a pharmaceutically acceptable carrier.
[00111] In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from the group consisting of 1-4, la-ld, 2a-2d, 4a-4d, and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from conjugates 1-4 and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from conjugates la, lb, 1c and Id and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from conjugates 2a, 2b, 2c and 2d and a pharmaceutically acceptable carrier. In another embodiment, the
pharmaceutical composition comprising at least one conjugate selected from conjugates 4a, 4b, 4c and 4d and a pharmaceutically acceptable carrier.
[00112] In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from the group consisting of 1-4 and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from the group consisting of 5-10 and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from the group consisting of 1-15 and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from the group consisting of 16a-16d and a pharmaceutically acceptable carrier.
[00113] In another embodiment, the pharmaceutical composition comprising at least one conjugate 31a and 31b and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from conjugates Cla-Clb and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from conjugates 1-218 and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least one conjugate selected from conjugates (B)-(F) and a pharmaceutically acceptable carrier.
[00114] In another embodiment, the pharmaceutical composition comprising at least two conjugates selected from the group consisting of 1-4, la-ld, 2a-2d, 4a-4d, and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition comprising at least three conjugates selected from conjugates 1-4, la-ld, 2a-2d, 4a-4d, and a pharmaceutically acceptable carrier.
[00115] In some embodiments, provided herein, a pharmaceutical composition comprising at least one conjugate selected from the group consisting of 1-4, la-ld, 2a-2d, 4a-4d, and a pharmaceutically acceptable carrier.
[00116] The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
[00117] The term "carrier" refers to a diluent, solvent, adjuvant, solubilizers, excipient, or vehicle with which the therapeutic compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water, alcohols and oils, including those of petroleum, animal, vegetable or
synthetic origin, such as peanut oil, soybean oil, mineral oil, castor oil, sesame oil and the like, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents.
[00118] For intravenous administration of a therapeutic compound, water, Saline solutions and aqueous dextrose and glycerol solutions can also be employed.
[00119] According to a certain embodiment, the formulation comprising the conjugates of this invention for intravenous administration is an aqueous isotonic solution. In some embodiments, the pharmaceutically acceptable carrier of the composition described herein can be a buffered saline solution, a buffered dextrose solution, or a buffered glycerol solution having a pH of 3-8. Each represent a separate embodiment of this invention.
[00120] According to a certain embodiment, the composition described herein for intravenous administration is an aqueous isotonic solution. In some embodiments, the pharmaceutically acceptable carrier of conjugates the conjugates described herein can be a buffered saline solution, a buffered dextrose solution, or a buffered glycerol solution having a pH of 3-8. Each represent a separate embodiment of this invention.
[00121] In another embodiments, the buffer of the compositions described herein solution can be any pharmaceutically acceptable buffer in the range of 3-8. In another embodiments, the buffer solution of the conjugates of this invention can be any pharmaceutically acceptable buffer in the range of 3-8. In another embodiment, various buffers having a pK of 3-8 can be employed for adjusting the pH of conjugates (I), (A)-(F), 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Cld, more preferably conjugates 1-4 solution such as, for example, ACES (N-(acetamido)-2- aminoethansulfonic acid); Acetate; N-(2-acetamido)-2-iminodiacetic acid; BES (N,N-bis[2- hydroxyethyl]-2-aminoethansulfonic acid); Bicine (2-(Bis(2-hydroxyethyl)amino)acetic acid); Bis-Tris methane (2-[Bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-l,3-diol); Bis-Tris propane (l,3-bis(tris(hydroxymethyl)methylamino)propane); Carbonate; Citrate; 3,3-dimethyl glutarate; DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxypropansulfonic acid); N- ethylmorpholine; Glycerol-2-phosphate; Glycine; Glycine-amid; HEPBS (N-(2- hydroxyethyl)piperazin-N’-4-buthanesulfonic acid); HEPES (N-(2-hydroxyethyl)piperazin-N’-2- ethanesulfonic acid); HEPPS (N-(2-hydroxyethyl)piperazine-N’-(3-propanesulfonic acid)); HEPPSO (N-(2-hydroxyethyl)piperazine-N’-(2-hydroxypropanesulfonic acid); Histidine; Hydrazine; Imidazole; Maleate; 2-methylimidazole; MES (2-(N-morpholino)ethanesulfonic acid); MOBS (4-(N-morpholino)-butanesulfonic acid); MOPS (3-(N-morpholino)-propanesulfonic acid; MOPSO (3-(N-morpholino)-2-hydroypropanesulfonic acid); Oxalate; Phosphate; Piperazine; PIPES (1,4-Piperazine-diethanesulfonic acid); POPSO (Piperazine-N,N’-bis(2-
hydroxypropanesulfonic acid)); Succinate; Sulfite; TAPS (3-[[l,3-dihydroxy-2- (hydroxymethyl)propan-2-yl]amino]propane-l-sulfonic acid); TAPSO (3-[[l,3-dihydroxy-2- (hydroxymethyl)propan-2-yl] amino] -2-hydroxypropane-l -sulfonic acid); Tartaric acid; TES (2- [[l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]amino]ethanesulfonic acid); THAM (Tris) (2- Amino-2-hydroxymethyl-propane-l,3-diol); and Tricine (N-(2-Hydroxy-l,l- bis(hydroxymethyl)ethyl)glycine). In another embodiment, the buffer is a sulfonic acid derivative buffer including, but not limited to, ACES, BES, DIPSO, HEPBS, HEPES, HEPPS, HEPPSO, MES, MOBS, MOPS, MOPSO, PIPES, POPSO, Sulfite, TAPS, TAPSO, and TES buffer. Each represent a separate embodiment of this invention.
[00122] In another embodiment, the buffer is a carboxylic acid derivative buffer including, but not limited to, Acetate, N-(2-acetamido)-2-iminodiacetic acid, 2-(Bis(2- hydroxyethyl)amino)acetic acid, Carbonate, Citrate, 3,3-dimethyl glutarate, Lactate, Maleate, Oxalate, Succinate, and Tartaric acid buffer. In another embodiment, the buffer is an amino acid derivative buffer including, but not limited to, Bicine, Glycine, Glycine-amid, Histidine, and Tricine buffer. Each represent a separate embodiment of this invention.
[00123] In another embodiment, the buffer is a phosphoric acid derivative buffer including, but not limited to, Glycerol-2-phosphate and phosphate buffer.
[00124] In one embodiment, the buffered saline for the compositions described herein can be, for example, Hank’s balanced salt solution, Earle’s balanced salt solution, Gey’s balanced salt solution, HEPES buffered saline, phosphate buffered saline, Plasma-lyte, Ringer’s solution, Ringer Acetate, Ringer lactate, Saline citrate, or Tris buffered saline. Each represent a separate embodiment of this invention.
[00125] In one embodiment, the buffered dextrose solution of the compositions of this invention can be, for example, acid-citrate-dextrose solution or Elliott’s B solution.
[00126] In some embodiments, the solutions for injection of the compositions of this invention is Plasma-Lyte A or Compound Sodium Lactate or similar.
[00127] In some embodiments, the compositions of this invention are formulated to a form selected from solutions, suspensions, emulsion, nanoparticles, liposomes, complexes, tablets, pills, capsules, powders, dragees, lozenges, liquids, gels, syrups, slurries, suspensions, emulsions, aerosol spray, sustained-release formulations, intranasal formulations, transdermal formulations, inhalations and the like. Each represents a separate embodiment of this invention.
[00128] In some embodiments, the composition of this invention can be formulated as a suppository, with traditional binders and carriers such as triglycerides, microcrystalline cellulose, gum tragacanth or gelatin. Each represent a separate embodiment of this invention.
[00129] In some embodiments, the pharmaceutical composition further comprises pharmaceutical excipients including, but not limited to, sodium chloride, potassium chloride, magnesium chloride, sodium gluconate, sodium acetate, calcium chloride, sodium lactate, and the like. In another embodiment, the composition contains sugar alcohols, wetting or emulsifying agents, and pH adjusting agents. In another embodiment, the composition further comprises chelating agents such as ethylenediaminetetraacetic acid; and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned. Other excipients such as solubilizers, stabilizers, surfactants, bulking agents, lyoprotectants, emulsifiers, complexing agents, dispersing agents, tonicity adjustment buffering agents and polymers could be included in the pharmaceutical compositions. In another embodiment, the surfactants are selected from derivatives of Castor oil (Polyoxyethylene Castor Oil Derivatives), Polyoxylglycerides, etc.
In other embodiments, the polymers are Polyvinylpyrrolidones, polyoxamers (linear polymers) etc.
[00130] In some embodiments, the pharmaceutical compositions of this invention are formulated for parenteral administration. In another embodiment, the pharmaceutical composition for parenteral administration is formulated as suspensions of the active compounds. Such suspensions may be prepared as oily injection suspensions or aqueous injection suspensions. For oily suspension injections, suitable lipophilic solvents or vehicles can be used including fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds, to allow for the preparation of highly concentrated solutions.
[00131] In some embodiments, for transmucosal and transdermal administration, penetrants and permeation enhancers appropriate to the barrier to be permeated may be used in the formulation. Such penetrants, including for example DMSO or polyethylene glycol, are known in the art.
[00132] In some embodiments, for oral administration, the compounds (or conjugates) of this invention are formulated readily by combining the active compounds with pharmaceutically acceptable carriers and excipients well known in the art. Such carriers enable the compounds or conjugate of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups,
slurries, suspensions, and the like, for oral ingestion by a subject. Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
[00133] In some embodiment, the pharmaceutical composition is further formulated with enteric coating which is useful to prevent exposure of the compounds of the invention to the gastric environment.
[00134] In some embodiments, the pharmaceutical composition of this invention for oral administration includes push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
[00135] In some embodiments, the pharmaceutical composition of this invention is formulated in a form of soft capsules, where the active compound may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
[00136] In some embodiments, the pharmaceutical compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, grinding, pulverizing, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
[00137] In some embodiments, the dosage of a composition to be administered will depend on many factors including the subject being treated, the stage of cancer, the route of administration, and the judgment of the prescribing physician.
Therapeutic use
[00138] In some embodiments, provided herein is a pharmaceutical composition comprising any one of the conjugates disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[00139] In some embodiments, provided herein is a pharmaceutical composition comprising at least one of the conjugates disclosed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[00140] In some embodiments, the present invention provides a method of treating a neoplastic disease comprising administering to a subject in need of such treatment a pharmaceutical composition comprising a therapeutically effective amount of a conjugate represented by a the structure at least one of the following conjugates: (I), (A)-(F) , 1-218, la-ld, 2a-2d, 31a, 31b, 16a- 16d, 4a-4d, and Cla-Clb, or combination thereof or isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The neoplastic disease can be selected from hematological cancers or non-hematological cancers.
[00141] In some embodiments, provided herein, a method of treating a cancer or a pre-cancerous condition or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of at least one of the conjugates disclosed herein represented by a the structure any one of the following conjugates: (I), (A)-(F) , 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Clb, or a pharmaceutically acceptable salt thereof, as described herein above, and a pharmaceutically acceptable carrier.
[00142] In another embodiment, the cancer is metastases cancer. In another embodiment, the cancer is a non-solid tumor or a solid tumor or a combination thereof. In another embodiment, the solid tumor comprises tumors in the central nervous system (CNS), liver cancer, colorectal carcinoma, breast cancer, gastric cancer, pancreatic cancer, bladder carcinoma, cervical carcinoma, head and neck tumors, vulvar cancer, and dermatological neoplasms. In another embodiment, the non-solid tumor comprises leukemias, lymphomas, and multiple myeloma. [00143] In another embodiment, the cancer is selected from the group consisting of hematological cancers and non-hematological cancers.
[00144] In another embodiment, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS) including, but not limited to, myeloid leukemia, lymphocytic leukemia, e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Non-Hodgkin's lymphoma, multiple myeloma, and Waldenstrom's macroglobulinemia. In another embodiment, the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS).
[00145] In another embodiment, said leukemia is selected from the group consisting of Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia
(CML), and Chronic Lymphoblastic Leukemia (CLL). In another embodiment, said lymphoma is selected from the group consisting of Hodgkin’s lymphoma and non-Hodgkin’s lymphoma.
[00146] In another embodiment, the term "Myelodysplastic Syndromes" (MDS) refers to a heterogeneous group of hematopoietic malignancies characterized by blood cytopenias, ineffective hematopoiesis and a hypercellular bone marrow. The MDSs are preleukemic conditions in which transformation into acute myeloid leukemia (AML) occurs in approximately 30-40% of cases. Unless allogenic stem cell transplantation can be offered, MDS is generally considered to be an uncurable condition.
[00147] Non-hematological cancers also known as solid tumors include, but are not limited to, sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor leiomydsarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, astrocytoma, Kaposi's sarcoma, and melanoma. Each possibility represents a separate embodiment of the invention.
[00148] Non-hematological cancers include cancers of organs, wherein the cancer of an organ includes, but is not limited to, breast cancer, bladder cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, lung cancer, cervical cancer, pancreatic cancer, prostate cancer, testicular cancer, thyroid cancer, ovarian cancer, brain cancer including ependymoma, glioma, glioblastoma, medulloblastoma, craneopharyngioma, pinealoma, acustic neuroma, hemangioblastoma, oligodendroglioma, menangioma, neuroblastoma, retinoblastoma, and their metastasis. Each possibility represents a separate embodiment of the invention.
[00149] In some embodiments, provided herein, a method of treating a cancer or a pre-cancerous condition or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a conjugate represented by the structure of at least one of conjugate (I), (A)- (F) , 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Clb, or combination thereof, or isomer thereof, or a pharmaceutically acceptable salt thereof, as described herein above, and a pharmaceutically acceptable carrier,.
[00150] In some embodiments, the pharmaceutical composition of this invention is administered by any suitable administration route selected from the group consisting of parenteral and oral administration routes. According to some embodiments, the route of administration is via parenteral administration. In various embodiments, the route of administration is intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal or intradermal administration route. In another embodiment, the pharmaceutical composition of this invention is administered via parenteral, oral, intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intradermal, or inhalation administration route. Each represent a separate embodiment of this invention. In another embodiment, the pharmaceutical composition is administered orally or parenterally. In another embodiment, the pharmaceutical composition is administered intravenously, intravenously, intraarterially, intramuscularly, subcutaneously, intraperitoneally, intracerebrally, intracerebroventricularly, intrathecally or intradermally.
[00151] For example, the pharmaceutical compositions can be administered systemically, for example, by intravenous (i.v.) or intraperitoneal (i.p.) injection or infusion. According to a certain embodiment, the pharmaceutical composition is administered by intravenous infusion for 30 minutes to 2 hours, such as for 1 hour. In some embodiments, the compositions of this invention are administered locally.
[00152] Toxicity and therapeutic efficacy of the compounds and conjugates described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e. g., by determining the IC50 (the concentration which provides 50% inhibition of cell growth) and the MTD (Maximal tolerated dose in tested animals) for a subject compound. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human subjects. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition (See e.g., Fingl, et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch. 1 pp. 1).
[00153] In some embodiments, the pharmaceutical composition comprising conjugate (I) is administered at a daily dose of 0.1-0.3 g/m2, 0.3-0.6 g/m2, 0.6-1.0 g/m2, 1.0-1.5 g/m2, 1.5-3 g/m2, 3.-5 g/m2, 5-8 g/m2, or 8-10 g/m2. Each embodiment represents a separate embodiment of this invention. In some embodiments, the pharmaceutical composition comprising conjugate (A), (B), (C), (D), (E), or (F), or one of conjugates represented by 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, Cla-Cld, or a pharmaceutically acceptable salt thereof is administered at a daily dose of
0.1-0.3 g/m2, 0.3-0.6 g/m2, 0.6-1.0 g/m2, 1.0-1.5 g/m2, 1.5-3 g/m2, 3.-5 g/m2, 5-8 g/m2, or 8-10 g/m2. Each possibility represents a separate embodiment of this invention.
[00154] In some embodiments, the pharmaceutical composition of this invention comprising at least one of conjugate represented by the structure of at least one of (I), (A)-(F), 1-218, la-ld, 2a- 2d, 31a, 31b, 16a-16d, 4a-4d, Cla-Cld or isomer thereof, or a pharmaceutically acceptable salt thereof, is administered in a daily dose ranging from about 0.1 g/m2 to about 10 g/m2 of the subject’s surface area. In some embodiments, the pharmaceutical composition of this invention comprising at least one of conjugate (I), (A)-(F), 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, Cla-Cld, is administered in a daily dose ranging from about 0.3 g/m2 to about 10 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 1 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 1.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 2 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 2.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 3 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 3.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 4 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 4.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.3 g/m2 to about 5 g/m2 of the subject’s surface area.
[00155] In another embodiment, the daily dose ranging from about 0.5 g/m2 to about 2.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 1 g/m2 to about 2.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 1 g/m2 to about 3.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 1 g/m2 to about 5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 2 g/m2 to about 5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 5 g/m2 to about 10 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.5 g/m2 to about 5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.5 g/m2 to about
4.5 g/m2 of the subject’s surface area. In another embodiment, the daily dose ranging from about 0.5 g/m2 to about 1.5 g/m2, from about 1.5 g/m2 to about 2.5 g/m2, from about 2.5 g/m2 to about
3.5 g/m2, from about 3.5 g/m2 to about 4.5 g/m2, from about 4.5 g/m2 to about 5.5 g/m2, from about
0.5 g/m2 to about 10 g/m2, from about 1 g/m2 to about 10 g/m2 of the subject’s surface area. Each represent a separate embodiment of this invention.
[00156] In one embodiment, the pharmaceutical composition comprising Compounds 1-5 is administered in a daily dose ranging from about 0.3 g/m2 to about 10 g/m2 of the subject’s surface area. Each represent a separate embodiment of this invention.
[00157] In another embodiment, the pharmaceutical composition comprising at least one of conjugates 1-4, la-ld, 2a-2d, 4a-4d, or isomer thereof is administered at a daily dose ranging from about 0.5 g/m2 to about 5 g/m2 of the subject’s surface area. In another embodiment, the pharmaceutical composition comprising at least one of conjugates 1-4 la-ld, 2a-2d, 4a-4d, or isomer thereof is administered at a daily dose ranging from about 0.5 g/m2 to about 5 g/m2 of the subject’ s surface area. In another embodiment, the pharmaceutical composition comprising at least one of conjugates 1-4 la-ld, 2a-2d, 4a-4d, or isomer thereof is administered at a daily dose ranging from about 0.5 g/m2 to about 4.5 g/m2 of the subject’s surface area.
[00158] In another embodiment, the pharmaceutical composition comprising at least one of conjugates 1-4, la-ld, 2a-2d, 4a-4d, or isomer thereof is administered at a daily dose ranging from about 0.5 g/m2 to about 2.5 g/m2 of the subject’s surface area.
[00159] According to some embodiments, the pharmaceutical composition comprising at least one of conjugate (I), (A)-(F) , 1-218, la-ld, 2a-2d, 31a, 31b, 16a-16d, 4a-4d, and Cla-Clb, or combination thereof, or isomer thereof, or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4 4.5, 4.6, 4.7, 4.8, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 g/m2 of the subject’s surface area. Each possibility represents a separate embodiment of the invention.
[00160] In another embodiment, the pharmaceutical composition comprising at least one conjugate 1, 2, 3, 4, la, lb, 1c, Id, 2a, 2b, 2c, 2d, 4a, 4b, 4c, 4d, or isomer thereof, or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 0.3, 0.5, 0.8, 1, 1.5, 2, 2.3, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10 g/m2 of the subject’s surface area. Each possibility represents a separate embodiment of the invention.
According to other embodiments, the pharmaceutical composition comprising at least two conjugates selected from 1, 2, 3, 4, la, lb, 1c, Id, 2a, 2b, 2c, 2d, 4a, 4b. 4a, 4b, 4c, 4d or isomer thereof or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 0.3, 0.5, 0.8, 1, 1.5, 2, 2.3, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10 g/m2 of the subject’s surface area. Each possibility represents a separate embodiment of the invention. According to other embodiments,
the pharmaceutical composition comprising di-Asp-Ara-C, is administered at a daily dose of about 0.3, 0.5, 0.8, 1, 1.5, 2, 2.3, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10 g/m2 of the subject’s surface area. Each possibility represents a separate embodiment of the invention.
[00161] In some embodiments, the pharmaceutical composition of this invention is administered at a daily dose of at least 0.1 g/m2.
[00162] According to some embodiments, the pharmaceutical composition comprising at least one of conjugate represented by the structure of (I), (A)-(F) , 1-218, la-ld, 2a-2d, 31a, 31b, 16a- 16d, 4a-4d, and Cla-Clb, or isomer thereof, or a pharmaceutically acceptable salt thereof is administered by intravenous infusion at a daily dose ranging from 0.3 g/m2 to 10.0 g/m2 of the subject’s surface area.
[00163] In another embodiment, the pharmaceutical composition of this invention administered by intravenous infusion at a daily dose ranging from 0.3 g/m2 to 10 g/m2 , from 0.3 g/m2 to 1 g/m2, from 0.3 g/m2 to 1.5 g/m2, from 0.3 g/m2 to 2 g/m2, from 0.3 g/m2 to 2.5 g/m2, from 0.3 g/m2 to 3 g/m2, from 0.3 g/m2 to 3.5 g/m2, from 0.3 g/m2 to 4.5 g/m2, from 0.3 g/m2 to 5 g/m2, from 0.5 g/m2 to 1 g/m2, from 0.5 g/m2 to 1.5 g/m2, from 0.5 g/m2 to 2 g/m2, from 0.5 g/m2 to 2.5 g/m2, from 0.5 g/m2 to 3.5 g/m2, from 0.5 g/m2 to 4.5 g/m2, from 0.5 g/m2 to 5 g/m2, from 0.3 g/m2 to 5.5 g/m2, from 0.3 g/m2 to 6 g/m2, from 0.5 g/m2 to 6 g/m2, from 0.5 g/m2 to 7 g/m2, from 0.5 g/m2 to 8 g/m2, from 0.5 g/m2 to 9 g/m2, from 0.5 g/m2 to 10 g/m2, from 1 g/m2 to 3 g/m2, from 1 g/m2 to 5 g/m2, from 1 g/m2 to 6 g/m2, from 1 g/m2 to 7 g/m2, from 1 g/m2 to 8 g/m2, from 1 g/m2 to 9 g/m2, from 1 g/m2 to 10 g/m2 of the subject’s surface area.
[00164] According one embodiment, the pharmaceutical composition comprising at least one conjugate 1, 2, 3, 4, la, lb, 1c, Id, 2a, 2b, 2c, 2d, or isomer thereof is administered by intravenous infusion at a daily dose ranging from 0.3 g/m2 to 10.0 g/m2 of the subject’s surface area. Each possibility represents a separate embodiment of the invention.
[00165] According to some embodiments, the pharmaceutical composition of this invention is administered at least once a month. According to additional embodiments, the pharmaceutical composition is administered at least twice a month. According to further embodiments, the pharmaceutical composition is administered at least once a week. According to yet further embodiments, the pharmaceutical composition is administered at least twice a week. According to yet further embodiments, the pharmaceutical composition is administered at least thrice a week. According to still further embodiments, the pharmaceutical composition is administered once a day for at least one week. According to further embodiments, the pharmaceutical composition is administered at least once a day for at least one week or until the subject is cured.
[00166] According to some embodiments, the pharmaceutical composition disclosed in this invention, is administered once a day for at least 2, 3, 4, 5, 6, 8, 10, 12, or at least 14 consecutive days once a month. Each represent a separate embodiment of this invention. In another embodiment, the pharmaceutical composition of this invention is administered once a day for at least 2, 3, 4, 5, 6, or 12 days twice a month, or further alternatively the pharmaceutical composition is administered every day or twice a week until the patient is cured. According to some embodiments, the pharmaceutical composition is administered once a day for at least 2, 3, 4, 5, 6, 8, 10, 12, or at least 14 consecutive days once a month. Alternatively, the pharmaceutical composition is administered once a day for at least 2, 3, 4, 5, 6, or 12 days twice a month, or further alternatively the pharmaceutical composition is administered every day or twice a week until the patient is cured.
[00167] In some embodiments, where the pharmaceutical composition is used for preventing recurrence of cancer, the pharmaceutical composition may be administered regularly for prolonged periods of time according to the clinician’s instructions.
[00168] In some cases, it may be advantageous to administer a large loading dose followed by periodic (e.g., weekly) maintenance doses over the treatment period. The compounds can also be delivered by slow-release delivery systems, pumps, and other known delivery systems for continuous infusion. Dosing regimens may be varied to provide the desired circulating levels of a particular compound based on its pharmacokinetics. Thus, doses are calculated so that the desired circulating level of a therapeutic agent is maintained.
[00169] Typically, the effective dose is determined by the activity and efficacy of the compound and the condition of the subject as well as the body weight or surface area of the subject to be treated. The dose and the dosing regimen are also determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the compounds in a particular subject.
[00170] According to additional embodiments, the subject being treated is a subject of 50 or more years of age, such as of 60, 70, 75 or more years of age. Each possibility represents a separate embodiment of the invention.
[00171] According to further embodiments, the compound of the invention is administered in a daily dosage of at least 2, 3, 5, 10, 15, 20, or at least 30 times greater than the maximal standard of care dose of cytarabine alone. Each possibility represents a separate embodiment of the invention. The following examples are to be considered merely as illustrative and non-limiting in nature. It will be apparent to one skilled in the art to which the present invention pertains that many
modifications, permutations, and variations may be made without departing from the scope of the invention.
[00172] In some embodiments, where the pharmaceutical composition is used for preventing recurrence of cancer, the pharmaceutical composition may be administered regularly for prolonged periods of time according to the clinician’s instructions.
[00173] In some cases, it may be advantageous to administer a large loading dose followed by periodic (e.g., weekly) maintenance doses over the treatment period. The compounds can also be delivered by slow-release delivery systems, pumps, and other known delivery systems for continuous infusion. Dosing regimens may be varied to provide the desired circulating levels of a particular compound based on its pharmacokinetics. Thus, doses are calculated so that the desired circulating level of a therapeutic agent is maintained.
[00174] Typically, the effective dose is determined by the activity and efficacy of the compound and the condition of the subject as well as the body weight or surface area of the subject to be treated. The dose and the dosing regimen are also determined by the existence, nature, and extent of any adverse side effects that accompany the administration of the compounds in a particular subject.
Pharmaceutical Salt
[00175] The term “pharmaceutical salt” as used herein refers to “pharmaceutically acceptable salts” of drug substances according to IUPAC conventions. Pharmaceutical salt is an inactive ingredient in a salt form combined with a drug. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the conjugates of the general formula (I), (A)-(F), 1-218, conjugates la-ld, 2a-2d, 4a-4d, 16a-16d, 31a, 31b, and Cla-Cld or isomer thereof, or any other salt form encompassed by the generic formula, which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral, base, acid or salt as described herein. Acid salts are also known as acid addition salts.
[00176] Pharmaceutical salts such as are known in the art (Stahl and Wermuth, 2011, Handbook of pharmaceutical salts, second edition), the contents of which are hereby incorporated by reference in their entirety, are exemplified herein below in some non-limiting embodiments.
[00177] In one embodiment, the pharmaceutically acceptable salt form is created from an organic or inorganic acid or residue of an acid, selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, trifluoroacetic acid, methaphosphoric acid,
camphorsulfonic acid, toluenesulfonic acid, para- toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, cyclamic acid, di(t-butyl)-naphthalenesulfonic acid, di(t-butyl)- naphthalenedisulfonic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, glycerophosphoric acid, hydrobromic acid, hydroiodic acid, 2 -hydroxy-ethanesulfonic (isethionic) acid, medronic (bisphosphonic) acid, methaphosphoric acid, naphthalene- 1,5-disulfonic acid, naphthalene-2- sulfonic acid and nitric acid. Each possibility represents a separate embodiment of the present invention.
[00178] In another embodiment, the pharmaceutically acceptable salt of the conjugate of this invention is a salt of a strong acid. In another embodiment, the pharmaceutically acceptable salt of conjugate (I), (A), (B), (C), (D), (E), (F), 1-218, la-ld, 2a-2d, 4a-4d, 16a-16d, 31a, 31b, Cla-Cld is a salt of a strong acid. In another embodiment, the pharmaceutically acceptable salt is hydrochloride salt. In another embodiment, the pharmaceutically acceptable salt is methanesulfonic acid.
Definitions
[00179] For convenience and clarity certain terms employed in the specification, examples and claims are described herein.
[00180] As used herein any “amino acid” refer to amino acid residue.
[00181] The term “amino acid residue” refers to an amino acid excluding the functional group that was used to attach the amino acid in forming the amino acid-drug conjugate, or amino acidcytarabine, or amino acid-amino acid conjugate.
[00182] The term “Ara-C” refers to cytarabine
[00183] The terms “BST-236”, “Astarabine” or “aspacytarabine” are referring to (S)-2-amino-4- ((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2- dihydropyrimidin-4-yl)amino)-4-oxobutanoic acid.
[00184] The terms “Ara-C with two aspartic acids”, “cytarabine with two aspartic acids”, “diaspartic cytarabine”, “di-aspartyl-cytarabine”, “di-aspartate-cytarabine”, “Asp-Ara-C-Asp”, “di- Asp-Ara-C”, “Ara-C di-aspartic” or “di-Asp-Cyt” refers to a composition comprising at least one conjugate selected from 1-4, la-ld, 2a-2d, 4a-4d, or isomer thereof.
[00185] The term "therapeutically effective amount" of the compound is that amount of the compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered. An effective amount of the compound may vary according to factors such as the disease state, age, sex, and weight of the individual.
[00186] The terms "treatment", "treat", "treating" and the like, are meant to include slowing, arresting or reversing the progression of a disease. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disease, even if the disease is not actually eliminated and even if progression of the disease is not itself slowed or reversed. A subject refers to a mammal, preferably a human being.
[00187] The term “residue of a drug” refers to a drug excluding the functional group that is used to attach the amino acids for the formation of the amino acids-drug conjugate.
[00188] The term “amino acid” refers to native or synthetic, L or D amino acids which are available commercially or are available by routine synthetic methods. Each possibility represents a separate embodiment of the present invention.
[00189] According to one embodiment the amino acids of this invention are an L configuration, D configuration or mixture thereof. Each possibility represents a separate embodiment of the present invention.
[00190] The amino acid AA1, AA2, and AA3 may be an a-amino acid, P-amino acid, y-amino acid, 6-amino acid or s-amino acid, with each possibility represents a separate embodiment of the present invention.
[00191] The term "ester” as used herein refers to a -C=(O)-O- or -O-C=(O)-, where the points of attachment are through both the C-atom and O-atom. One or both oxygen atoms of the ester group can be replaced with a sulfur atom, thereby forming a "thioester" , i.e., a -C=(O)-S-, -C=(S)-O- or -C=(S)-S- group.
[00192] The term “amide” refers to the group -C=(O)-N-, -N-C=(O)- wherein the points of attachments are through the carbon atom on one hand, and through the nitrogen atom on the other. As used herein, the term “amine”, used alone or as part of another group, refers to any primary, secondary, tertiary or quaternary amine.
[00193] As used herein, the term "isomer thereof" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The three-dimensional structures are called configurations. Therefore, any one of the structure of conjugates (I), (A)-(F) and 1-218, la-ld, 2a-2d, 4a-4d, 31a, 31b, 16a-16d, Cla- Clb or isomers thereof include a single enantiomer, a diastereomer, a racemic mixture, cis configuration or a trans configuration.
[00194] The term “about” in reference to a numerical value stated herein is to be understood as the stated value +/- 10%.
[00195] The term “pharmaceutically acceptable salt” of a drug refers to a salt according to IUPAC conventions. Pharmaceutically acceptable salt is an inactive ingredient in a salt form combined with a drug. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral, base, acid or salt. Acid salts are also known as acid addition salts.
[00196] The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
[00197] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents.
Synthetic Methods
[00198] In the conjugate, according to the present invention, the drug is covalently attached to the amino acid or amino acid analog. The skilled artisan will be able to optimize the appropriate linkage and position of the drug moiety within the compound. Various concerns should be taken into consideration to guide the artisan in this decision, such as selection of the specific drug, selection of the derivatives, selection of the position of attachment to the drug species, and requirements concerning host intracellular enzymes for drug activation.
[00199] Thus, in accordance with another aspect, the present invention provides a method for preparing a conjugate (I), wherein the process comprises:
(i) mixing an amino acid with coupling reagent in a solvent;
(ii) adding D to the mixture of (i) and stirring; and
(iii) optionally adding another amino acid (or the same as (i)) with coupling reagent in a solvent.
[00200] In some embodiments, the present invention provides a method for preparing a conjugate (I), wherein the process comprises:
(i) mixing an amino acid with coupling reagent in a solvent;
(ii) adding D to the mixture of (i) and stirring; and
(iii) optionally adding protected amino acid (the same or different amino acid as (i)), with coupling reagent in a solvent; and
(iv) deprotecting the protecting groups to afford the product.
[00201] In some embodiments, the present invention provides a method for preparing a conjugate (I), wherein the process comprises:
(i) mixing a protected amino acid with coupling reagent in a solvent;
(ii) adding D to the mixture of (i) and stirring; and
(iii) optionally adding an amino acid (the same or different amino acid as (i)), with coupling reagent in a solvent; and
(iv) deprotecting the protecting groups to afford the product.
[00202] Thus, in accordance with another aspect, the present invention provides a method for preparing a conjugate (I), wherein the process comprises:
(i) mixing a protected amino acid with coupling reagent in a solvent;
(ii) adding D to the mixture of (i) and stirring;
(iii) optionally adding another protected amino acid (or the same as (i)) with coupling reagent in a solvent; and
(iv) deprotecting the protecting groups to afford the product.
[00203] In another embodiment, the protected amino acid refers to at least one protecting group attached to any functional group available for protection on the amino acid
[00204] In another embodiment, D of stage (ii) is a protected drug of this invention, wherein the protected drug refers to at least one protecting group that is attached to any functional group available for protection on the amino acid. In another embodiment, the solvent of stage (i) and (ii) is an organic or inorganic solvent. In another embodiment, the solvent is an organic solvent. In another embodiment, the solvent is an inorganic solvent. In another embodiment, the solvent is DMF (dimethylformamide), DCM (dichloromethane), DMA (dimethylacetamide), NMP (N- methyl-2-pyrrolidone), 2-pyrrolidone or DMI (l,3-Dimethyl-2-imidazolidinone). Each represent a separate embodiment of this invention. In another embodiment, the solvent is DMF
[00205] In some embodiments, the deprotecting step of the amino and COOH protecting groups is conducted under H2, in an organic solvent or an aqueous solution or mixture thereof,
[00206] In another embodiment, the deprotecting step is conducted under H2 in a mixture of an organic solvent and an acidic aqueous phase.
[00207] In another embodiment, the deprotection step is conducted by organic or inorganic acid. In another embodiment, the deprotection step is conducted by organic or inorganic base.
[00208] In another embodiment, the deprotecting step is conducted in a mixture of an organic solvent and an aqueous phase.
[00209] In some embodiments, the present invention provides a method 1 for preparing a Conjugates (A)-(F) and 1-15 wherein R4 is the same as R1 and/or R2 and/or R3 and /or R5 wherein the process comprises:
(i) mixing a protected amino acid (at least two equivalents) with a coupling reagent in a solvent;
(ii) adding cytarabine (one equivalent) to the mixture of (i) and stirring; and
(iii) deprotecting the protecting groups to afford the product; wherein the protected amino acid comprises at least one protecting group.
[00210] In some embodiments, the present invention provides a method 2 for preparing a Conjugates (A)-(F) and 1-218 wherein the process comprises:
(i) mixing a protected amino acid with a coupling reagent in a solvent;
(ii) adding cytarabine to the mixture of (i);
(iii) adding another portion of the same or different protected amino acid with coupling reagent in a solvent; and
(iv) deprotecting the protecting groups to afford the product; wherein the protected amino acid comprises at least one protecting group.
[00211] In some embodiments, the method for the preparation of conjugate I and methods 1 and 2 described herein include a step of adding a cytarabine. In one embodiment, the cytarabine is a protected cytarabine, wherein the protected cytarabine refers to at least one protecting group attached to any functional group available for protection on the amino acid.
[00212] In some embodiments, the removal of the protecting group of methods (I), (1) and (2), can be after any step.
[00213] In some embodiments, the mixing step in the method for the preparation of conjugate I and methods 1 and 2 described herein are conducted at room temperature.
[00214] In another embodiment, the solvent used in the method for the preparation of conjugate I and methods 1 and 2 described herein is an organic or inorganic solvent. In another embodiment, the solvent is an organic solvent. In another embodiment, the solvent is selected from DMF (dimethylformamide), DCM (dichloromethane), DMA (dimethylacetamide), NMP (N-methyl-2- pyrrolidone), 2-pyrrolidone or DMI (l,3-Dimethyl-2-imidazolidinone). Each represent a separate embodiment of this invention. In another embodiment, the solvent is DMF
[00215] In some embodiments, the coupling reagent used in the process of this invention is selected from but not limited to EDOHC1, HOBt x-hydrate, BOP (Benzo triazole- 1-yl-oxy-tris- (dimethylamino)-phosphonium hexafluorophosphate), CDI (N,N'-carbonyldiimidazole), COMU (l-[(l-(Cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)] uronium hexafluorophosphate), DCC (N,N'-dicyclohexylcarbodiimide), DIC (N,N'- diisopropylcarbodiimide), EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide), DEPBT (3- (Diethoxy -phosphoryloxy)- 1, 2, 3-benzo[d]triazin-4(3H)-one), HATU, HBTU (2-(lH-
B enzo triazole- 1-yl)- 1,1, 3, 3 -tetramethyluronium hexafluorophosphate), HCTU (O-(lH-6- Chlorobenzo triazole- 1-yl)- 1,1, 3, 3 -tetramethyluronium hexafluorophosphate), MS NT (1- (Mesitylene-2-sulfonyl)-3-nitro-lH-l,2,4-triazole ), PyBOP (Benzo triazole- 1-yl-oxy-tris- pyrrolidino-phosphonium hexafluorophosphate), PyBroP (Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate), TBTU (2-( 1H-B enzo triazole- 1 -yl)- 1 , 1 ,3, 3 -tetramethy laminium tetrafluoroborate), TFFH (Tetramethylfluoroformamidinium hexafluorophosphate), and TOTU (O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N’,N’, -tetramethyluronium).
[00216] For example, for the purpose of illustration and not for limitation, conjugates (1) (Aspartic acid-cytarbine-aspartic conjugates) or 16 (Aspartic acid-cytarbine-Glutamic acid conjugates) can be prepared by reacting Aspartic acid or Glutamic acid which are protected on the amine and carboxyl, with the cytarabine or an activated and/or protected derivative thereof in the presence of a coupling reagent, followed by deprotection.
[00217] Cytarabine may be unprotected or protected at any available functional group (e.g., OH, NH2, carboxyl etc.), with any one of the protecting groups described herein.
[00218] In another embodiment, the deprotecting step in the method for the preparation of conjugate I and methods 1 and 2 described herein include a reagent capable of removing the protecting group(s).
[00219] In another embodiment, the deprotecting step in the method for the preparation of conjugate I and methods 1 and 2 described herein include a reagent capable of removing the protecting group(s) and further form a salt of the obtained conjugate.
[00220] The protecting groups - used on amino acid or drug such as cytarabine can be any protecting group known to a person of skill in the art. The term “protecting group” refers to chemical residues used to block reactive sites during chemical synthesis, that enable chemical reaction to be carried out selectively at one reaction site in a multifunctional compound, other reactive sites must be temporarily blocked. The residues used to block these reactive sites called protecting groups.
[00221] The protecting group can be a hydroxyl protecting group, an amino protecting group, a carboxy protecting group, etc. As used herein, the term "OH protecting group" or "hydroxy protecting group" refers to a readily cleavable group bonded to hydroxyl groups. As used herein, the term "NH protecting group" or "amino protecting group" refers to a readily cleavable group bonded to amino groups. As used herein, the term "carboxy protecting group" refers to a readily cleavable group bonded to carboxy groups.
[00222] According to one embodiment, the protecting group is selected from group of acetamidomethyl (Acm), acetyl (Ac), acetonide, adamantyloxy (AdaO), alfa-allyl (OA11), Alloc, benzoyl (Bz), benzyl (Bzl), benzyloxy (BzlO), benzyloxycarbonyl (Z), benzyloxymethyl (Bom), bis-dimethylamino (NMe2), 2-bromobenzyloxycarbonyl (2-Br-Z), t-butoxy (tBuO), t- butoxycarbonyl (Boc), t-butoxymethyl (Bum), t-butyl (tBu), t-butylthio (tButhio), 2- chlorobenzyloxycarbonyl (2-C1-Z), 2-chlorotrityl (2-Cl-Trt), cyclohexyloxy (cHxO), 1- cyclopropyl-l-methyl-ethyl (Dmcp), 2,6-dichlorobenzyl, 4,4’-dimethoxybenzhydryl (Mbh), 1- (4,4-dimethyl-2,6-dioxo-cyclohexylidene)-3-methylbutyl (ivDde), 4{N-[l-(4,4-dimethyl-2,6- dioxo-cyclohexylidene)-3 -methylbutyl] -amino] benzyloxy (ODmab), 2,4-dinitrophenyl (Dnp), fluorenylmethoxycarbonyl (Fmoc), formyl (For), Mesitylene-2- sulfonyl (Mts), 4-methoxybenzyl, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), 4-methoxytrityl (Mmt), 4-methybenzyl (MeBzl), 3-methylpent-3-yl (Mpe), 1 -methyl- 1-phenyl-ethyl (PhiPr), Methyl, 4-methyltrityl (Mtt), 3-nitro-2-pyridinesulfenyl (Npys), 2,2,4,6,7-pentamethyl-dihydrobenzofurane-5-sulfonyl (Pbf), 2,2,5,6,8-pentamethyl-chromane-6-sulfonyl (Pmc), tosyl (Tos), trifluoroacetyl (Tfa), trimethylacetamidomethyl (Tacm), Triphenylmethyl (trityl, Trt) and Xanthyl (Xan). Each possibility represents a separate embodiment of the present invention.
[00223] A non-limiting example of a hydroxyl protecting group is an acyl group (COR wherein R=alkyl, aryl, etc.). A currently preferred acyl group is an acetyl group (i.e., OR' = acetate, OAc). Another example of a hydroxy protecting group is a silyl group, which can be substituted with alkyl (trialkylsilyl), with an aryl (triarylsilyl) or a combination thereof (e.g., dialkylphenylsilyl). A preferred example of a silyl protecting group is trimethylsilyl (TMS) or di-t-butyldimethyl silyl (TBDMS), triisopropylsilyl (TIPS), triethylsilyl (TES). Other examples of hydroxy protecting groups include, for example, C1-C4 alkyl, -CO-(Ci-Ce alkyl), -SO2-(Ci-Ce alkyl), -SO2-aryl, -CO- Ar in which Ar is an aryl group as defined above, and -CO-(Ci-Ce alkyl)-Ar (e.g., a carboxybenzyl (Bz) group).
[00224] Examples of amino-protecting groups include carbamates as t-butoxycarbonyl (BOC), benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc) and amides as acetamide and
benzamide. Examples of hydroxy protecting groups include ethers such as methyl, methoxymetyl (MOM), benzyloxymethyl (BOM) and benzyl (Bn), esters such as formate, acetate and benzoate and silyl ethers which can be substituted with alkyl (trialkylsilyl), with an aryl (triarylsilyl) or a combination thereof (e.g., dialkylphenylsilyl), e.g., trimethylsilyl (TMS) or t-butyldimethyl silyl (TBDMS). Other examples of hydroxy protecting groups include, for example, C1-C4 alkyl (e.g., methyl, ethyl, propyl, butyl and the like), -CH2PI1 (benzyl or Bn), allyl (All), (allyl)-CO-(Ci-C6 alkyl), -SO2-(Ci-C6 alkyl), -S 02-ary 1-CO- Ar in which Ar is an aryl group as defined above, and - CO-(Ci-Ce alkyl)Ar (e.g., a carboxybenzyl (Bz) group). Other examples of hydroxy protecting groups include acid sensitive protecting groups such as tetrahydropyranyl (THP), methoxymethyl (MOM), triphenylmethyl (Trityl) and dimethoxy trityl (DMT). Each possibility represents a separate embodiment of the present invention.
[00225] Representative carboxy-protecting groups include, but are not limited to, methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), trimethylsilyl (TMS), t- butyldimethylsilyl (TBDMS), diphenylmethyl (benzhydryl, DPM) and the like. Protecting groups may be removed by deprotecting agents which, according to the principles of the present invention, are preferably the same as the pharmaceutical salt moiety. In certain embodiments the pharmaceutical acids suitable for removal of acid labile protecting groups are: acetic acid, aceturic, 4-acetamido-benzoic, adipic, aminohippuric, 4-amino-salicylic, ascorbic, alginic, aspartic, benzenesulfonic, benzoic, boric, butyric, capric (decanoic), caproic (hexanoic), carbonic, citric, camphoric, camphorsulfonic, caprylic (octanoic), cyclamic, cinnamic, 2,2-dichloro-acetic, di(t- butyl)-naphthalenesulfonic, di(t-butyl)-naphthalenedisulfonic, dehydroacetic, diatrizoic, dodecylsulfuric, ethane- 1,2-disulfonic, edetic, ethanesulfonic, 2-ethyl-hexanoic, erythorbic, formic, fumaric, galactaric (mucic), gentisic, glucaric, glucoheptanoic, gluconic, glucuronic, glutamic, glutaric, glycerophosphoric, glycolic, hippuric, hydrochloric, hydrobromic, hydroiodic, 2-(4-hydroxybenzoyl)-benzoic, 2-hydroxy-ethanesulfonic (isethionic), l-hydroxy-2-naphtoic, isobutyric, lactic, lactobionic, lauric, iodoxamic, isostearic, maleic, malic, malonic, mandelic, medronic, methanesulfonic, methaphosphoric, methylboronic, myristic, naphthalene- 1,5- disulfonic, naphthalene-2-sulfonic, nicotinic, nitric, oleic, orotic, oxalic, 2-oxo-glutaric (ketoglutaric), palmitic, pamoic (embonic), pentetic, propionic, propanoic, pyroglutamic, pyruvic, phosphoric, saccharine, salicylic, sebacic, sorbic, stearic (octadecanoic), suberic, succinic, sulfuric, tartaric, thiazoximic, thiocyanic, toluenesulfonic, trifluoroacetic and undecylenic (undec - 10-enoic) acids. Each possibility represents a separate embodiment of the present invention.
[00226] Other suitable protecting groups are described, e.g., in Wuts and Greene, 2007, “Greene’ s protective groups in organic synthesis”, Fourth edition, the contents of which are incorporated by reference herein.
[00227] In specific embodiments, the pharmaceutically acceptable acid that reacts with the precursor compound of steps (iii), (vi), or (x) removes the protecting group is selected from the group consisting of methanesulfonic acid, hydrochloric acid, phosphoric acid, toluenesulfonic acid, para- toluenesulfonic acid, benzenesulfonic acid, and sulfuric acid. In accordance with such embodiments, the resulting salt is selected from the group consisting of, hydrochloride, methanesulfonate, phosphate, toluenesulfonate, benzensulfonate, sulfate, each possibility represents a separate embodiment of the present invention.
[00228] In certain embodiments the pharmaceutical bases suitable for removal of base labile protecting groups are: aluminum hydroxide, ammonia, arginine, benethamine, benzathine, betaine, t-butylamine (erbumine), calcium hydroxide, choline hydroxide, deanol, diethylamine, 2- diethylamino-ethanol, diethanolamine, ethanolamine, ethylenediamine, hydrabamine, 4-(2- hydroxy ethyl) morpholine, l-(2-hydroxy ethyl)- pyrrolidine (epolamine), imidazole, lithium hydroxide, lysine, N-methylglucamine (meglumine), magnesium hydroxide, 4- phenylcyclohexylamine, piperazine, potassium hydroxide, sodium hydroxide, tromethamine, and zinc hydroxide. Each possibility represents a separate embodiment of the present invention.
[00229] In other embodiments, H2 Pd/C may be used as a deprotecting agent when the protecting group is, e.g., benzyl or trityl.
[00230] While it is preferred that the protecting group be removed by a pharmaceutical salt creating compound, the present invention is not limited to such embodiments. It is apparent to a person of skill in the art that the protecting group can be removed by other deprotecting agents, and the salt form of the drug may be generated in a separate, subsequent step.
EXAMPLES
The following abbreviations are used in the Examples:
BOC: t-butyloxycarbonyl
DIEA: diisopropylethylamine
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
EDC: l-Ethyl-3 -(3 -dimethylaminopropyl) carbodiimide
HOBt: N-hydroxybenzo triazole
HPLC: High performance liquid chromatography
MS: Mass spectrometry
MTT: 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide
OtBu: t-butyl ester
MTBE: Methyl tertiary butyl ether
TEAB: triethylammonium bicarbonate
TFA: trifluoroacetic acid
EXAMPLE 1 (Method A)
[00231] Synthesis of conjugate la - (S)-2-amino-4-(((2R,3S,4S,5R)-5-(4-((S)-3-amino-3- carboxypropanamido)-2-oxopyrimidin-l(2H)-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-4-oxobutanoic add (N,5’-O-diaspartyl-cytarabine)
[00232] Boc-Asp-OtBu (579 mg, 2 mmol), EDOHC1 (479 mg, 2.5 mmol) and HOBt hydrate (306 mg, 2 mmol) were dissolved in DMF (8 ml) and stirred at room temperature for Ihr. Ara-C (243 mg, 1 mmol) was added and the reaction mixture were stirred for 12 hr at room temperature. The mixture was evaporated to leave an oily residue which was dissolved in ethyl acetate (40 ml). The organic phase was extracted with 5% NaHCOa (3 xl5 ml) followed by washing with HC1 solution (0. IM, 15 ml) and 5M NaCl (15 ml). The ethyl acetate layer was separated, dried (MgSCU) and evaporated. The residue was subjected to Boc and t-Bu groups deprotection with a cleavage solution (20 ml of TFA with 2.5% H2O). The reaction mixture was mixed for 3hr and then the 60 ml solution was transferred slowly to 240 ml ice cold MTBE resulting in precipitation of a white powder. The precipitate was filtered off (sinter glass), washed with MTBE and dried. The product was dissolved in AcOH, reprecipitated by addition of MTBE, collected and washed with MTBE. The powder was dried and analyzed by HPLC and MS. HPLC analysis on Primesep 100 column
using gradient of acctonitrilc/HaO with 0.1%TFA show peak at retention time of 20-21 min. Spectrophotometer measurement, show optical density at wavelengths: 214, 247, 299 nm. m/z: 473.14
Method B
[00233] Boc-Asp-OtBu (289 mg, 1 mmol), EDOHC1 (230 mg, 1.2 mmol) and HOBt hydrate (153 mg, 1 mmol) were dissolved in DMF (4 ml) and stirred at room temperature for Ihr. Ara-C (243 mg, 1 mmol) was added and the reaction stirred for 12 hr at room temperature. To the reaction mixture was added a second portion of Boc-Asp-OtBu (289 mg, Immol), EDOHC1 (230 mg, 1.2 mmol) and HOBt hydrate (153 mg, 1 mmol) in DMF (4 ml). The reaction mixture was stirred for 12 hr at room temperature. The mixture was evaporated to oily residue, dissolved with ethyl acetate (40 ml) and extracted with 5% NaHCOa (3 x 15 ml), 0.1M HC1 (15 ml) and 5M NaCl (15 ml). The ethyl acetate was evaporated, the residue was dissolved in 4.0 M HC1 in dioxane and stirred for Ihr to allow Boc and t-Bu groups removal. Water was added and the reaction mixture was stirred overnight after which the product was precipitated as white crystals, filtered on sinter glass, washed with dioxane, dried and analyzed by HPLC and MS. HPLC analysis on Primesep 100 column as done in Method A showed the same product.
EXAMPLE 2
Synthesis of conjugate 16a - (S)-2-amino-5-(((2R,3S,4S,5R)-5-(4-((S)-3-amino-3- carboxypropanamido)-2-oxopyrimidin-l(2H)-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-5-oxopentanoic add. (N-aspartyl-5’-O-glutamyl-cytarabine)
[00234] Boc-Asp-OtBu (289 mg, Immol), EDOHC1 (192 mg, 1 mmol) and HOBt hydrate (153 mg, 1 mmol) were dissolved in DMF (4 ml) and was stirred at room temperature for Ihr. Ara-C (243 mg, Immol) was added and the reaction mixture was stirred for 12hr at room temperature. The mixture was evaporated to oily residue, dissolved in ethyl acetate (40 ml), extracted with 5% NaHCOa (3 xl5ml) followed by extraction with 0. IM HC1 (15ml) and washed with 5M NaCl
(15ml). The organic layer was separated, dried (MgSC ) and evaporated to leave a residue which was dissolved in 4ml DMF. Boc-Glu-OtBu (303 mg, Immol), EDC*HC1 (191 mg, 1 mmol) and HOBt hydrate (153 mg, 1 mmol) were dissolved in 4 ml DMF and was stirred at room temperature for Ihr after which it was added to the reaction mixture and stirred for 12hr at room temperature. The reaction mixture was evaporated to oily residue, dissolved in ethyl acetate (40 ml), extracted with 5% NaHCCF (3 xl5 ml) and 0.1M HC1 (15ml) and washed with 5M NaCl (15ml). The ethyl acetate phase was evaporated, and the residue was subjected to Boc and tBu groups deprotection with TFA containing 2.5% H2O for 3 hr. The resulting solution (60 ml) was transferred slowly into 240 ml ice cold MTBE while stirring resulting in precipitation of white solid which was collected on sinter glass, washed with MTBE and dried, m/z: 487.16
EXAMPLE 3
Synthesis of Conjugate 31a - N4-(l-((2R,3S,4S,5R)-5-(((L-alanyl)oxy)methyl)-3,4- dihydroxytetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)-L-asparagine (N- aspartyl-5 ’ -O-alanyl-cytarabine)
[00235] Boc-Asp-OtBu (289 mg, Immol), EDC*HC1 (191 mg, 1 mmol) and HOBt hydrate (153 mg, 1 mmol) were dissolved in 4 ml DMF and was stirred at room temperature for Ihr. Ara-C (243 mg, Immol) was added and the reaction mixture was stirred for 12hr at room temperature. Boc- Ala-OH (378.4 mg, 2mmol), EDC*HC1 (479 mg, 2.5 mmol) and HOBt hydrate (306 mg, 2 mmol) were dissolved in 8 ml DMF and stirred for Ihr after which the mixture was added to the reaction mixture and stirred for 12hr at room temperature. The mixture was evaporated to oily residue, dissolved in ethyl acetate (40 ml), extracted with 5% NaHCOa (3 xl5ml) followed by extraction with 0. IM HC1 (15ml) and washed with 5M NaCl (15ml). The organic layer was separated, dried (MgSOa) and evaporated to leave a residue which was subjected to Boc and tBu groups deprotection with TFA containing 2.5% H2O for 3 hr. The resulting solution (60 ml) was transferred slowly into 240 ml ice cold MTBE while stirring resulting in precipitation of white
solid which was collected on sinter glass, washed with MTBE and dried. The powder was dried and analyzed by HPLC and MS. HPLC analysis on Primesep 100 column using gradient of acetonitrile/PEO with 0.1%TFA show peak at retention time of 21-22min. Spectrophotometer measurement, show optical density at wavelengths: 213, 246, 300 nm. m/z: 429.14
EXAMPLE 4
Synthesis of Conjugate Cla - (S)-2-amino-5-(((2R,3S,4S,5R)-5-(4-((S)-4-amino-4- carboxybutanamido)-2-oxopyrimidin-l(2H)-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)-5-oxopentanoic add (N,5’-O-glutamyl-cytarabine)
[00236] Boc-Glu-OtBu (303 mg, Immol), EDC*HC1 (191 mg, 1 mmol) and HOBt (153 mg, 1 mmol) were dissolved in 4 ml DMF and were stirred for Ihr at room temperature. Ara-C (243 mg, Immol) was added, and the reaction mixture was stirred for 12hr at room temperature. A second portion of Boc-Glu-OtBu (303 mg, Immol), EDC*HC1 (191 mg, 1 mmol) and HOBt (153 mg, 1 mmol) were dissolved in 4 ml DMF and were stirred for Ihr at room temperature after which the mixture was added into the first reaction mixture and stirred for 12hr at room temperature. The mixture was evaporated to oily residue, dissolved in ethyl acetate (40 ml), extracted with 5% NaHCOa (3 xl5ml) followed by extraction with 0. IM HC1 (15ml) and washed with 5M NaCl (15ml). The organic layer was separated, dried (MgSO- and evaporated to leave a residue which was subjected to Boc and tBu groups deprotection with TFA containing 2.5% H2O for 3 hr. The resulting solution (60 ml) was transferred slowly into 240 ml ice cold MTBE while stirring resulting in precipitation of white solid which was collected on sinter glass, washed with MTBE and dried. The powder was dried and analyzed by HPLC and MS. HPLC analysis on Primesep 100 column using gradient of acetonitrile/H2O with 0.1%TFA show peak at retention time of 20- 21 min. m/z: 501.17
EXAMPLE 5 Synthesis of conjugate lb
(S)-2-amino-4-(((2R,3S,4S,5R)-5-(4-((S)-2-amino-3-carboxypropanamido)-2-oxopyrimidin- l(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)-4-oxobutanoic acid
[00237] Cytarabine was coupled with excess of 4.2 eq. of Boc-Asp-OtBu in the presence of EDC*HC1 and HOBt, the reaction was worked-up and the crude reside obtained was purified on silica gel, followed by Boc and OtBu Deprotection in TFA and preparative-HPLC purification resulted in four compounds at RRT -1.15, -2.7, -3.2 and -3.3, that have the same molecular weight - 473 Da. One of which is the cpd. of Example 1.
EXAMPLE 6 Synthesis of conjugate 2a (S)-2-amino-4-(((2R,3S,4S,5R)-5-(4-((S)-2-amino-3-carboxypropanamido)-2-oxopyrimidin- l(2H)-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)-4-oxobutanoic acid
Conjugate 2a was obtained from the chromatographic separation of Example 5.
EXAMPLE 7
Synthesis of Conjugate 4a
(S)-3-amino-4-(((S)-l-carboxy-3-((l-((2R,3S,4S,5R)-3,4-dihydroxy-5-
(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-l,2-dihydropyrimidin-4-yl)amino)-3- oxopropyl)amino)-4-oxobutanoic add
[00238] Conjugate 4a was obtained from the chromatographic separation of Example 5.
EXAMPLE 8
HPLC Purification of di-aspartate-cytarabine
[00239] The purification of di-aspartate-cytarabine was performed using reverse phase high performance liquid chromatography (RP-HPLC) on semi-preparative Merck Hitachi HPLC detected with L 4000 UV detector. Column used was Primesep 100 column, dimension 10x250mm, particle- 5pm, 100A, with acetonitrile/H2O gradient as shown below. Injection volume: 1 ml (100 mg di-aspartyl-cytarabine in 1 ml H2O), fraction collection: 3 ml each fraction, wave length: 240 nm, flow: 3 ml/min.
HPLC solution composition:
Solution A: H2O: 0.1% TFA
Solution B: 9:1 Acetonitrile: H2O: 0.1%TFA
The anticipated retention time of di-aspartyl-cytarabine is in the range of 66-70 min.
EXAMPLE 9
Analytical methods of di-aspartate-cytarabine
A. HPLC analysis
[00240] After synthesis completion sample of the batch were analyzed using reverse phase high performance liquid chromatography (RP-HPLC) on Merck Hitachi HPLC. The analysis was performed on analytical HPLC with L4000 UV detector at 240 nm. Samples were analyzed on Primesep 100 column, dimension 4.6x250mm, 5pm, 100A, analysis was performed with acetonitrile/ H2O gradient as shown below), flow rate: 0.75 ml/min.
Solution composition:
Solution A: H2O: 0.1% TFA
Solution B: 9:1 Acetonitrile: H2O: 0.1%TFA
In some embodiments, in Figure 1, HPLC analysis of of Conjugate lb is shown. HPLC chromatogram of BST-236 (RT 5.444 minutes) and lb (RT 16.643 minutes). Conjugate lb is detected at 247 nm, with 92.8 area% purity.
B. Spectrophotometer analysis
[00241] The UV analysis was performed V-630 (Jasco, Japan) spectrophotometer. 1 mg of di- aspartate-cytarabine was dissolved in 1 ml H2O, this solution was diluted to a ratio of 1:100 in
H2O. The spectrum measurement was performed by scan between 190-340 nm. The analysis shows optical density (O.D.) peaks anticipated at: 214, 247, 299 nm (Figure 2).
C. Mass Spectrometer analysis
[00242] In some embodiments, Figure 3 shows analysis of Conjugate lb by Mass Spectrometer, indicating the molecular mass of the product as 473 g/mol. M.S. Analysis of di-aspartate- cytarabine was performed on MALDI-TOF mass spectrometer. The MS analysis show the anticipated MW=473 g/mol [474=473+lH].
EXAMPLE 10
Effect of Aspartate- Cytarabine- Aspartate on leukemia cell lines
[00243] The effect of the purified sample from Example 8 - Aspartate-Cytarabine-Aspartate (di- aspartate-cytarabine) on different cell lines was evaluated. Briefly, various cell lines were obtained from ATCC or ECACC. Hematological cells were grown in RPMI medium containing 10-20% FBS and 1% glutamine. Cells were seeded into 96-well plates, 50,000 cells/ml, 0.2 ml per well. Test substances were diluted in saline or PBS and added in final concentrations of 0.1 nM to 10 pM, in a volume of 20 pl. The study was conducted in triplicates, PBS was used as control. Plates were incubated for 72hr at 37°C, 5% CO2. At the end of the exposure period, an MTT assay using the MTT reagent [3-(4,5-dimethylthiazol-2-yl)2,5 diphenyltetrazolium bromide] was performed. MTT was added to each well at a concentration of 5 mg/ml in a volume of 0.02 ml. Plates were incubated at 37°C for 3h. The plates were centrifuged at 3500 rpm for 5 minutes and the supernatant was aspired. The pellets which contained MTT crystals were each dissolved in 0.2 ml DMSO. Absorbance was determined using ELISA reader at a wavelength of 570 nm.
[00244] Figure 4 shows the effect of Ara-C with two aspartic acids in-vitro on human and mice leukemia cell growth. Both MOLT-4 and L1210 cell growth is inhibited by Ara-C with two aspartic acids.
[00245] The results demonstrated that both human and mice leukemia cells are sensitive to di- aspartyl-cytarabine. The activity of Ara-C with two aspartic acids in Molt-4 human leukemia cells is similar to aspacytarabineprodrug.
EXAMPLE 11
Stability of Aspartate-Cytarabine-Aspartate in media
[00246] 7mg Ara-C with two aspartic acids (the sample from Example 8) was weighted and dissolved with 1.4ml medium RPMI1640 solution. The mixture was incubated at 37°C for the
following times: Oh, 2h, 4h, 6h, 8h, 24h, 48h. At the end of incubation time, sample of 200pl was taken for analysis, the 200p I sample was dissolved in 1ml ammonium acetate buffer and analyzed by HPLC (described in Example 7). Results indicated in Figure 5 and Figure 6. The results in figure 5 show that the main degradation product of Ara-C with two aspartic acids is aspacytarabine which further continue to metabolise into cytarabine. This suggest that Ara-C with two aspartic acids is a pro-drug of cytarabine, and the results at Figure 6 show the stability of Ara-C with two aspartic acids C in RPMI medium with serum, in relative percentage (%) as compared to its degradation products: aspacytarabine and cytarabine.
[00247] While certain features disclosed have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the compounds and methods of use disclosed herein.
Claims (1)
- What is claimed is: A conjugate or a pharmaceutically acceptable salt thereof of a cytarabine residue and at least two amino acids, represented by the structure of Formula (A): isomer thereof, whereinR1, R2, R3 and R5 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine;R4 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine; and wherein at least one of R1, R2, R3 and R5 is an amino acid residue. The conjugate of claim 1, wherein the amino acid residue of R1, R2, R3, or R4 are each independently linked to the cytarabine through an a-carboxylic acid or a carboxylic acid side chain. The conjugate of claim 1, wherein the amino acid of R5 is linked to R4 through an a-amino, a-carboxylic acid or a carboxylic acid side chain. The conjugate of claim 1, wherein at least two of R1, R2, and R3 are different. The conjugate of claim 1, wherein at least two of R1, R2, and R3 are the same. The conjugate of claim 1, wherein if R1, R2, or R3 is an amino acid residue, then the amino acid residue is the same as R4. The conjugate of claim 1, wherein if R1, R2, or R3 is an amino acid residue, then the amino acid residue is different than R4. The conjugate of claim 1, wherein R4 and R5 are the same amino acid residue. The conjugate of claim 1, wherein R4 and R5 are each a different amino acid residue. The conjugate of claim 1, wherein R1, R2, and R3 are each independently H or amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine,66 glutamine, and alanine, wherein at least one of R1, R2, or R3 is not H, and R5 is H. The conjugate of claim 1, wherein R1, R2, and R3 are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. The conjugate or a pharmaceutically acceptable salt of any one of claims 1-11, wherein R4 is an aspartic acid residue (Asp), and at least one of R1, R2, R3, or R5 is not H, as represented by Formula (B): isomer thereof. The conjugate of claim 12, wherein R1, R2, and R3 are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, wherein at least one of R1, R2, or R3 is not H, and R5 is H. The conjugate of claim 12, wherein R1, R2, and R3 are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. The conjugate of any one of claims 12-14, wherein R1, R2, R3 and R5 are each independently H or an aspartic acid residue. The conjugate of any one of claims 12- 15, wherein R1 is an aspartic acid residue. The conjugate of any one of claims 12-15, wherein R2 is an aspartic acid residue. The conjugate of any one of claims 12-15, wherein R3 is an aspartic acid residue. The conjugate of any one of claims 12 and 14-15, wherein R5 is an aspartic acid residue. The conjugate of any one of claims 12, 14 and 19, wherein R1, R2, and R3 are H. The conjugate of any one of claims 12-15 and 19, wherein at least one of R1, R2, and R3 is aspartic acid. The conjugate of any one of claims 15-18, wherein R5 is H. The conjugate of any one of claims 12-19, wherein at least two of R1, R2, R3, and R5 are aspartic acid. The conjugate of any one of claims 12-14, wherein R1, R2, R3 and R5 are each independently H or a glutamic acid residue. The conjugate of any one of claims 12-14 and 24, wherein R1 is a glutamic acid residue. The conjugate of any one of claims 12-14 and 24, wherein R2 is a glutamic acid residue. The conjugate of any one of claims 12-14 and 24, wherein R3 is a glutamic acid residue. The conjugate of any one of claims 12-14 and 24, wherein R5 is a glutamic acid residue. The conjugate of claim 28, wherein R1, R2, and R3 are H. The conjugate of any one of claims 14 and 24, wherein at least one of R1, R2, and R3 is a glutamic acid. The conjugate of any one of claims 24-27, wherein R5 is H. The conjugate of any one of claims 12-14 and 24-29, wherein at least two of R1, R2, R3, and R5 are glutamic acid. The conjugate of any one of claims 12-14, wherein R1, R2, R3 and R5 are each independently H or an alanine residue. The conjugate of any one of claims 12-14 and 33, wherein R1 is an alanine residue. The conjugate of any one of claims 12-14 and 33, wherein R2 is an alanine residue. The conjugate of any one of claims 12-14 and 33, wherein R3 is an alanine residue. The conjugate of any one of claims 12-14 and 33, wherein R5 is an alanine residue. The conjugate of claim 37, wherein R1, R2, and R3 are H. The conjugate of any one of claims 14 and 33, wherein at least one of R1, R2, and R3 is an alanine residue. The conjugate of any one of claims 33-36, wherein R5 is H. The conjugate of any one of claims 12-14 and 33-37, wherein at least two of R1, R2, R3, and R5 are alanine residue. The conjugate or a pharmaceutically acceptable salt of any one of claims 1-11, wherein R4 is a glutamic acid residue (Glu) as represented by the structure of conjugate (C): or isomer thereof, wherein at least one of R1, R2, R3 and R5 is not hydrogen (H).68 The conjugate of claim 42 wherein R1, R2, and R3 are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, wherein at least one of R1, R2, or R3 is not H, and R5 is H. The conjugate of claim 42, wherein R1, R2, and R3 are each independently H or an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine, and R5 is an amino acid residue selected from group consisting of aspartic acid, glutamic acid, asparagine, glutamine, and alanine. The conjugate of any one of claims 1-44, wherein the pharmaceutically acceptable salt is a salt of an organic or inorganic acid selected from the group consisting of hydrochloric acid, methanesulfonic acid, phosphoric acid, trifluoroacetic acid, methaphosphoric acid, camphorsulfonic acid, toluenesulfonic acid, para- toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, cyclamic acid, di(t-butyl)-naphthalenesulfonic acid, di(t-butyl)- naphthalenedisulfonic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, glycerophosphoric acid, hydrobromic acid, hydroiodic acid, 2- hydroxy-ethanesulfonic (isethionic) acid, medronic (bisphosphonic) acid, methaphosphoric acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid and nitric acid. The conjugate of any one of claims 1-45, wherein the pharmaceutically acceptable salt is hydrochloride salt. The conjugate of any one of claims 1-46, wherein the pharmaceutically acceptable salt is methanesulfonic acid. A pharmaceutical composition comprising the conjugate of any one of claims 1-47 a pharmaceutically acceptable carrier. A method of treating a cancer or a pre-cancerous condition or disorder in a subject in need thereof, comprising administering the pharmaceutical composition of claim 48. The method of claim 49, wherein the cancer is metastases cancer. The method according to claim 49, wherein the cancer is a non-solid tumor or a solid tumor or a combination thereof. The method according to claim 49, wherein the solid tumor comprises tumors in the central nervous system (CNS), liver cancer, colorectal carcinoma, breast cancer, gastric cancer, pancreatic cancer, bladder carcinoma, cervical carcinoma, head and neck tumors, vulvar cancer, and dermatological neoplasms.69 The method according to claim 51, wherein the non-solid tumor comprises leukemias, lymphomas, and multiple myeloma. The method of claim 49, wherein the cancer is selected from the group consisting of hematological cancers and non-hematological cancers. The method of claim 54, wherein the hematological cancer is selected from the group consisting of leukemias, lymphomas, myelomas and Myelodysplastic Syndromes (MDS). The method of claim 55, wherein the leukemia is selected from the group consisting of Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphoblastic Leukemia (CLL). The method of claim 55, wherein the lymphoma is selected from the group consisting of Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. The method of any one of claims 49-57, wherein the pharmaceutical composition is administered via parenteral, oral, intravenous, intraarterial, intramuscular, subcutaneous, intraperitoneal, intracerebral, intracerebroventricular, intrathecal, intradermal, or inhalation administration route. The method of claim 58, wherein the pharmaceutical composition is administered orally or parenterally. The method of claim 59, wherein the pharmaceutical composition is administered intravenously, intravenously, intraarterially, intramuscularly, subcutaneously, intraperitoneally, intracerebrally, intracerebroventricularly, intrathecally or intradermally. The method of any one of claims 49-60, wherein Formula (I) is administered at a daily dose of 0.1-10 g/m2. The method of claim 61, wherein Formula (I) is administered at a daily dose of 0.1-0.3 g/m2, 0.3-0.6 g/m2, 0.6- 1.0 g/m2, 1.0- 1.5 g/m2, 1.5-3 g/m2, 3.-5 g/m2, 5-8 g/m2, or 8-10 g/m2. A dosage form comprising the composition of claim 48, wherein the composition is formulated in a dosage form selected from tablets, pills, dragees, lozenges, capsules, powders, liquids, gels, syrups, slurries, suspensions, solutions, emulsions, aerosol spray, sustained-release formulations and the like.70
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