WO2006104396A1 - Compositions antagonistes du cuivre pre-complexees - Google Patents

Compositions antagonistes du cuivre pre-complexees Download PDF

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WO2006104396A1
WO2006104396A1 PCT/NZ2006/000053 NZ2006000053W WO2006104396A1 WO 2006104396 A1 WO2006104396 A1 WO 2006104396A1 NZ 2006000053 W NZ2006000053 W NZ 2006000053W WO 2006104396 A1 WO2006104396 A1 WO 2006104396A1
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alkyl
copper
clo alkyl
clo
aryl
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Garth James Smith Cooper
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Protemix Corporation Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • 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
    • A61K31/04—Nitro compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Copper antagonists are pre-complexed with a non-copper metal ion prior to administration for therapy.
  • Metal ions used for pre-complexing are pharmaceutically acceptable and have a lower association constant for the copper antagonist than that of copper.
  • a metal ion for pre-complexing a copper antagonist that chelates Cu is one that has a lower binding affinity for the copper antagonist than Cu .
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of said subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase in copper (I), (8) decrease appetite, (9) decrease food intake, (10) lower body fat, (11) decrease fat uptake, for example, in the the gastrointestinal tract and/or (13) increase metabolism.
  • Such compositions include, for example, tablets, capsules, solutions and suspensions for parenteral and oral delivery forms and formulations.
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of said subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase in copper (I), and/or (8) increase anti-coagulation activity.
  • Such compositions include, for example, tablets, capsules, solutions and suspensions for parenteral and oral delivery forms and formulations.
  • the invention includes methods for administering a therapeutically effective amount of a pharmaceutically acceptable pre-complexed copper antagonist in a delayed release preparation, a slow release preparation, an extended release preparation, a controlled release preparation, and/or in a repeat action preparation.
  • Such preparations may be administered to a subject having or suspected of having or predisposed to diseases, disorders and/or conditions referenced herein.
  • Such compounds may be administered in amounts, for example, that are effective to (1) decrease body and/or tissue copper levels, (2) increase copper output in the urine of said subject, (3) decrease copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress (7) increase in copper (I), (8) a decrease in inflammation, (9) a decrease in plaque formation, (10) a decrease in homocysteine, and/or (11) a decrease in nerve dysfunction or nerve death.
  • Such compositions include, for example, tablets, capsules, solutions and suspensions for parenteral and oral delivery forms and formulations.
  • the invention includes transdermal patches, pads, wraps, and bandages capable of being adhered or otherwise associated with the skin of a subject, said articles being capable of delivering a therapeutically effective amount of a pharmaceutically acceptable pre-complexed copper antagonist to a subject.
  • the invention includes an article of manufacture comprising a vessel containing a therapeutically effective amount of a pharmaceutically acceptable pre-complexed copper antagonist and instructions for use, including use for the treatment of a subject.
  • the invention includes an article of manufacture comprising packaging material containing one or more dosage forms containing a pharmaceutically acceptable pre- complexed copper antagonist, wherein the packaging material has a label that indicates that the dosage form can be used for a subject having or suspected of having or predisposed to any of the diseases, disorders and/or conditions described or referenced herein.
  • dosage forms include, for example, tablets, capsules, solutions and suspensions for parenteral and oral delivery forms and formulations.
  • the invention includes a formulation comprising a pharmaceutically acceptable pre- complexed copper antagonist in amounts effective to remove copper from the body of a subject and reduce elevated.
  • Such formulations include, for example, tablets, capsules, solutions and suspensions for parenteral and oral delivery forms and formulations.
  • the invention includes devices containing therapeutically effective amounts of a pharmaceutically acceptable pre-complexed copper antagonist, for example, a rate- controlling membrane enclosing a drug reservoir and a monolithic matrix device. These devices may be employed for the treatment of subjects in need thereof as disclosed herein.
  • a pharmaceutically acceptable pre-complexed copper antagonist for example, a rate- controlling membrane enclosing a drug reservoir and a monolithic matrix device.
  • the patent is also directed to a method for assaying a pre-complexed copper antagonist drug candidate and, more specifically, to a method for measuring the binding interaction between a copper antagonist drug candidate and a non-copper metal ion to determine a binding interaction parameter of the copper antagonist drug candidate, and then comparing the binding interaction parameter against a predetermined copper antagonist correlation measurement (e.g., a mathematical expression) to estimate at least one pharmacokinetic parameter for said pre- complexed copper antagonist drug candidate.
  • a predetermined copper antagonist correlation measurement e.g., a mathematical expression
  • a "copper antagonist” is a pharmaceutically acceptable compound that binds or chelates copper, preferably copper (II), in vivo for removal. Copper chelators are presently preferred copper antagonists. Copper (II) chelators, and copper (II) specific chelators (i.e., those that preferentially bind copper (II) over other forms of copper such as copper (I)), are especially preferred. "Copper (II)” refers to the oxidized (or +2) form of copper, also sometimes referred to as Cu +2 .
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids the like.
  • salts may be prepared from pharmaceutically acceptable nontoxic acids, including inorganic and organic acids.
  • Organic acids include both aliphatic and aromatic carboxylic acids and include, for example, aliphatic monocarboxylic acids, aliphatic dicarboxylic acids, aliphatic tricarboxylic acids, aromatic monocarboxylic acids, aromatic dicarboxylic acids, aromatic tricarboxylic acids and other organic acids known to those of skill in the art.
  • Aliphatic dicarboxylic acids include saturated aliphatic dicarboxylic acids and unsaturated aliphatic dicarboxylic acids.
  • saturated aliphatic dicarboxylic acids include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, and sebacic acid.
  • unsaturated aliphatic dicarboxylic acids include maleic acid, fumaric acid, citraconic acid, mesaconic acid, itaconic acid and the like.
  • Aliphatic tricarboxylic acids includes saturated aliphatic tricarboxylic acids and unsaturated tricarboxylic acids.
  • saturated tricarboxylic acids include tricarballylic acid, 1, 2, 3-butanetricarboxylic acid and the like.
  • Suitable aliphatic dicarboxylic acids include those of the formula: HOOC-Q 1 -COOH, wherein Q 1 is alkylene of 1 to about 8 carbon atoms or alkenylene of 2 to about 8 atoms, and includes both straight chain and branched chain alkylene and alkenylene groups.
  • aromatic dicarboxylic acids include phthalic acid, isophthalic acid, terephthalic acid and the like.
  • aromatic tricarboxylic acids include trimesic acid, hemimellitic acid and trimellitic acid.
  • preventing means preventing in whole or in part, or ameliorating or controlling.
  • a "therapeutically effective amount” in reference to the compounds or compositions of the instant invention refers to the amount sufficient to induce a desired biological, pharmaceutical, or therapeutic result. That result can be alleviation of the signs, symptoms, or causes of a disease or disorder or condition, or any other desired alteration of a biological system. In the present invention, the result will involve the prevention, decrease, or reversal of tissue injury, in whole or in part, and prevention and/or treatment of the diseases, disorders and conditions referenced herein.
  • Therapeutic effects include, for example, (1) decreasing body and/or tissue copper levels, (2) increasing copper output in the urine, (3) decreasing copper uptake, for example, in the gastrointestinal tract, (4) decrease SOD, for example, EC-SOD, as measured by mass or activity, (5) decrease homocysteine, (6) decrease oxidative stress and/or (7) increase in copper (I).
  • treating refers to both therapeutic treatment and prophylactic or preventative measures.
  • Those in need of treatment include those already with the disorder as well as those prone to having the disorder, or those diagnosed with the disorder, or those in which the disorder is to be prevented.
  • a reduction in copper, particularly extracellular copper that is generally in its copper II form, will be advantageous in the treatment of disorders, diseases, and/or conditions, caused or exacerbated by mechanisms that may be affected by or are dependent on excess copper values and/or hyperglycemia.
  • Pre-complexed copper antagonist may be prepared for administration via oral delivery.
  • the preparation of various tablets and capsules are described in Examples 1-12. They include tablets (see, e.g., Example 1), tablets with a filler(s) (see, e.g., Example 2), tablets with a desiccant(s) (see, e.g., Example 3), tablets with a wet granulations binder(s) (see, e.g., Example 4), tablets with a wet granulations binder(s) and a desiccant(s) (see, e.g., Example 5), capsules (see, e.g., Example 6), capsules with a desiccant(s) (see, e.g., Example 7), capsules with a filler(s) (see, e.g., Example 8), capsules with a filler(s) and a granulation binder(s) (see, e.g., Example 9), capsules with
  • copper antagonists preferably copper (II) antagonists, and more preferably copper (II) chelator agents
  • Copper antagonists include, for example, trientine active agents, which include trientines (triethylenetetramines).
  • Trientine active agents may be prepared in a number of ways. Trientine is a strongly basic moiety with multiple nitrogens that can be converted into a large number of suitable associated acid addition salts using an acid, for example, by reaction of stoichiometrically equivalent amounts of trientine and of the acid in an inert solvent such as ethanol or water and subsequent evaporation if the dosage form is best formulated from a dry salt. Possible acids for this reaction are in particular those that yield physiologically acceptable salts.
  • Nitrogen-containing pre-complexed copper antagonists for example, trientine active agents such as, for example, trientine, that can be delivered as a salt(s) (such as acid addition salts, e.g., trientine dihydrochloride) act as pre-complexed copper-chelating agents or antagonists, which aids the elimination of pre-complexed copper from the body by forming a stable soluble complex that is readily excreted by the kidney.
  • inorganic acids can be used, e.g., sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid. This is not an exhaustive list.
  • organic acids can be used to prepare suitable salt forms, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono-or polybasic carboxylic, sulfonic or sulfuric acids, (e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 2 -hydroxy ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenemono-and-disulfonic acids, and laurylsulfuric acid).
  • trientine active agents include derivative trientines, for example, trientine in combination with picolinic acid (2-pyridinecarboxylic acid). These derivatives include, for example, trientine picolinate and salts of trientine picolinate, for example, trientine picolinate HCl. They also include, for example, trientine di- picolinate and salts of trientine di-picolinate, for example, trientine di-picolinate HCl.
  • Picolinic acid moieties may be attached to trientine, for example one or more of the CH 2 moieties, using chemical techniques known in the art. Those in the art will be able to prepare other suitable derivatives, for example, trientine-PEG derivatives, which may be useful for particular dosage forms including oral dosage forms having increased bioavailability.
  • Compounds suitable as copper antagonists include cyclic and acyclic compounds according to Formula I:
  • X 1 , X 2 , X 3 and X 4 are independently selected from the group consisting of N, S and O;
  • R 1, R 2> R 3; R 41 R 5 and R 6 may be functionalized for attachment to groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverab ⁇ lity and/or half lives of the constructs.
  • groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverab ⁇ lity and/or half lives of the constructs.
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO-peptide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG, Cl to ClO alkyl-S-peptide, and Cl to ClO alkyl-S-protein.
  • R 7 , Rg, R 9 , Rio, Rn and Ri 2 may be functionalized for attachment to groups which include, but are not limited to, peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • groups which include, but are not limited to, peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO-peptide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG, Cl to ClO alkyl-S-peptide and Cl to ClO alkyl-S-protein.
  • Suitable compounds of Formula I include those wherein Ri , R 2, R 3, R 45 R 5 and R 6 are independently selected from H, Cl to C6 alkyl, -CH 2 COOH, -CH 2 SO 3 H, -CH 2 PO(OH) 2 and -CH 2 P(CH 3 )O(OH); and each R 7, R 8, R 9, R 10, Rn and Ri 2 is independently selected from H and Cl to C6 alkyl.
  • suitable compounds include those wherein at least one of R 1 and R 2 and at least one of R 5 and R 6 is H or Cl to C6 alkyl.
  • R 3 and R 4 are selected from H or Cl to C6 alkyl; more particularly, Ri R 2, R 5, and R 6 are selected from H or Cl to C6 alkyl.
  • suitable compounds include those wherein X 2 and X 3 are N and nl, n2 and n3 are 2, or nl and n3 are 2 and n2 is 3.
  • Ri , R 6, R 7 , R 8, R 9 , R 10, Rn, and R 12 are independently selected from H and Cl to C3 alkyl.
  • all of Xi , X 2, X 3i and X 4 are suitably N or, alternatively, one of X 1 and X 4 is S and X 2 and X 3 are N or S.
  • Tetra-heteroatom acyclic compounds within Formula I are provided where Xi, X 2 , X 3 , and X 4 are independently chosen from the atoms N, S or O, such that, (a) for a four-nitrogen series, i.e., when X 1 , X 2 , X 3 , and X 4 are N then: R 1 , R 2 , R 3 ,
  • R 1 , R 2 , R 3 , R 4 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO- ⁇ e ⁇ tide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO- PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO- PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 6 does not exist;
  • R 1 , R 2 , R 3 , R 4 and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H 5 CH 2 PO(OH) 2 , CH 2 P(CHs)O(
  • R 1 , R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ' ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • R 4 does not exist and Ri
  • R 2 , R 3 , R 5 , and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(
  • R 1 , R 2 , R 3 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • R 7 , R 8 , R 9 , R 10 , R 115 or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • R 1 and R 6 do not exist;
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3- ClO cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH);
  • R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • R 7 , Rg, R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 3 and R 6 do not exist;
  • R 1 , R 2 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH);
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , Rio, Rn, or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • R 4 and R 6 do not exist;
  • R 1 , R 2 , R 3 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(
  • one or several OfR 1 , R 2 , R 3 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S- ⁇ e ⁇ tide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R ]0 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • R 3 and R 4 do not exist;
  • R 1 , R 2 , R 5 and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); n
  • one or several OfR 1 , R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alky 1-CO -peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH- ⁇ rotein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 2 , R 3 , R 4 , and R 5 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl, n2, n3,
  • R 2 , R 3 , R 4 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , Rib Ri 2> R 1 3 t> r R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO- ⁇ e ⁇ tide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl-ClO alkyl- S -protein, (b) for a three-nitrogen series, i.e., when X 1 , X 2 , X 3 , are N and X 4 is S or O then: R 5 does not exist; R 2 , R 3 , and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di
  • R 2 , R 3 or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 1 O, Rn, Ri 2> R1 3 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 2 and R 5 do not exist;
  • R 3 and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl, n2, n3,
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 2 , or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl- S -protein.
  • R 7 , R 8 , R 9 , Rio, Rn, Ri 2 , R 13 or R 14 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl- ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S- ⁇ rotein.
  • R 1 R 2 R 3 R 5 and R 6 may be functionalized for attachment to groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • groups which include, but are not limited to peptides, proteins, polyethylene glycols (PEGs) and other suitable chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include, but are not limited to, Cl to ClO alkyl-CO-peptide, Cl to ClO alkyl-CO-protein, Cl to ClO alkyl-CO-PEG, Cl to ClO alkyl-NH-peptide, Cl to ClO alkyl-NH-protein, Cl to ClO alkyl-NH-CO-PEG, Cl to ClO alkyl-S- ⁇ e ⁇ tide and Cl to ClO alkyl-S -protein.
  • suitable compounds of Formula I include those wherein R 1 , R 2 , R 3 , R 5 and R 6 are independently selected from H, Cl to C6 alkyl, -CH 2 COOH, -CH 2 SO 3 H, -CH 2 PO(OH) 2 and -CH 2 P(CH 3 )O(OH); and each R 7, R 8, R 9 and R 10 is independently selected from H and Cl to C6 alkyl.
  • suitable compounds include those wherein at least one Of R 1 and R 2 and at least one of R 5 and R 6 is H or Cl to W
  • R 1 , R 2 , R 3 , R 5 or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , or R 10 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • Examples of 40 such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-
  • ClO alkyl-CO-protein Cl-ClO alkyl-CO-PEG 5 Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl- ClO alkyl-S-protein.
  • R 3 does not exist;
  • R 1 , R 2 , R 5 or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl-ClO alkyl-S-protein.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl- S -peptide, and Cl-ClO alkyl-S-protein.
  • R 5 does not exist;
  • one or several OfR 1 , R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , or R 10 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and C 1 -C 10 alkyl-S-protein.
  • a series of tri-heteroatom cyclic analogues according to the above Formula II are provided in which R 1 and R 6 are joined together to form the bridging group (CR 11 R 12 ) I i 3 , and X 1 , X 2 and X 3 are independently chosen from the atoms N, S or O such that: 42
  • R 2 , R 3 , or R 5 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl- ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl- ClO alkyl- S -peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or R 12 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and C 1 -C 10 alkyl-S-protein.
  • R 5 does not exist;
  • R 2 , and R 3 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, Cl- 43 C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, Cl-
  • C6 alkyl fused aryl CH 2 COOH, CH 2 SO 3 H, CH 2 PO(OH) 2 , CH 2 P(CH 3 )O(OH); nl, n2, and n3 are independently chosen to be 2 or 3; and R 7 , R 8 , R 9 , R 10 , Rn, and R 12 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl.
  • R 2 or R 3 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half-lives of the constructs.
  • functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl- ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl- ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • R 7 , R 8 , R 9 , R 10 , R 11 , or Rj 2 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmacokinetics, deliverability and/or half lives of the constructs.
  • Examples of such functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • Copper antagonists useful in the invention also include copper chelators that have been pre-complexed with a non-copper metal ion prior to administration for therapy.
  • Metal ions used for pre-complexing have a lower association constant for the copper antagonist than that of copper.
  • a metal ion for pre-complexing a copper antagonist that chelates Cu 2+ is one that has a lower binding affinity for the copper antagonist than Cu 2+ .
  • metal complexes comprising copper antagonists and non- copper metals (that have lower binding affinities than copper for the copper antagonist) and one or more additional ligands than typically found in complexes of that metal.
  • additional ligands may serve to block sites of entry into the complex for water, oxygen, hydroxide, or other species that may undesirably complex with the metal ion and can cause degradation of the copper antagonist.
  • copper complexes of triethylenetetramine have been found to form pentacoordinate complexes with a tetracoordinated triethylenetetramine and a chloride ligand when crystallized from a salt solution rather than a tetracoordinate Cu triethylenetetramine complex.
  • X 1 , X 2 , X 3 , and X 4 are independently chosen from the atoms N, S or O such that: 4N series: when X 1 , X 2 , X 3 , and X 4 are N then: R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH, CH 2 SO 3 H, CH
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein. Also provided are embodiments wherein one, two, three or four Of R 1 through Ri 2 are other than hydrogen.
  • Variations of the syntheses used for the 4N series provide examples of the 3N series 1 class of compounds.
  • the chemistry described by Meares et al. can be modified to give examples of the 3NX series of compounds.
  • nl, n2, and n3 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, and n3 may be the same as or different than any other repeat;
  • nl, n2, and n3 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, and n3 may be the same as or different than any other repeat; and R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are independently chosen from H, CH 3 , C2-
  • R 1 , R 2 , Rs, or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • R 2 , R 3 or R 4 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • functionalization include but are not limited to Cl- ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl- NH-protein, Cl-ClO aikyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, Cl-ClO alkyl-S- protein.
  • R 3 and R 4 are independently chosen from H, CH 3 , C2-C10 straight chain or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, mono, di, tri, tetra and penta substituted aryl, heteroaryl, fused aryl, C1-C6 alkyl aryl, C1-C6 alkyl mono, di, tri, tetra and penta substituted 75 aryl, C1-C5 alkyl heteroaryl, C1-C6 alkyl fused aryl, CH 2 COOH,
  • nl, n2, n3, and n4 are independently chosen to be 2 or 3, and each repeat of any of nl, n2, n3 and n4 may be the same as or different than any other repeat; and
  • Triethylenetetramine itself has been synthesized by reaction of 2 equivalents of ethylene diamine with 1,2-dichloro ethane to give triethylenetetramine directly.
  • Meares et al. could be used. Standard peptide synthesis using the Rink resin along with FMOC protected natural and un-natural amino acids which can be conveniently 86 cleaved at the penultimate step of the synthesis generates a di-peptide C-terminal amide. This can be reduced using Diborane in THF to give the open chain tri-aza compounds as shown below:
  • Examples of such functionalization include but are not limited to Cl-ClO alkyl-CO-peptide, Cl-ClO alkyl-CO-protein, Cl-ClO alkyl-CO-PEG, Cl-ClO alkyl-NH-peptide, Cl-ClO alkyl-NH-protein, Cl-ClO alkyl-NH-CO-PEG, Cl-ClO alkyl-S-peptide, and Cl-ClO alkyl-S-protein.
  • one or several OfR 1 , R 2 , R 5 , or R 6 may be functionalized for attachment, for example, to peptides, proteins, polyethylene glycols and other such chemical entities in order to modify the overall pharmaco-kinetics, deliverability and/or half lives of the constructs.
  • X 1 , X 2 , and X 3 are independently chosen from the atoms N, S or O such that:
  • Multi- tablets may be formulated which include small spheroid-shaped compressed mini-tablets 114 that may have a diameter of between 3 to 4 mm and can be placed in a gelatin capsule shell to provide the desired pattern of pre-complexed copper antagonist release.
  • Each capsule may contain 8-10 minitablets, some uncoated for immediate release and others coated for extended release of the pre-complexed copper antagonist.
  • pre-complexed copper 124 antagonist form that is capable of providing the controlled delivery of pre- complexed copper antagonists in a predictable manner over a long period of time. See, e.g., Examples, 11, 12, 23, 24, 35, and 36 herein.
  • the pre-complexed copper antagonist reservoir may be composed of a conventional tablet, or a microparticle pellet containing multiple units that do not swell following contact with aqueous fluids.
  • the cores dissolve without modifying their internal osmotic pressure, thereby avoiding the risk of membrane rupture, and typically comprise 60:40 mixtures of lactulose: microcrystalline cellulose (w/w).
  • Active drug(s) is/are released through a two-phase process, comprising diffusion of aqueous fluids into the matrix, followed by 125 diffusion of the pre-complexed copper antagonist out of the matrix.
  • Multiple-unit membrane-controlled systems typically comprise more than one discrete unit.
  • thickening agents or binders include: the lipid type, among which are vegetable oils (cotton seed, sesame and groundnut oils) and derivatives of these oils (hydrogenated oils such as hydrogenated castor oil, glycerol behenate, the waxy type such as natural carnauba wax or natural beeswax, synthetic waxes such as cetyl ester waxes, the amphiphilic type such as polymers of ethylene oxide (polyoxyethylene glycol of high molecular weight between 4000 and 100000) or propylene and ethylene oxide copolymers (poloxamers), the cellulosic type (semisynthetic derivatives of cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, of high molecular weight and high viscosity, gum) or any other polysaccharide such as alginic acid, the polymeric type such as acrylic acid polymers (such as carbomers), and the mineral type such as colloidal silica and bentonite.
  • Formulations and/or compositions for topical administration of one or more compositions and formulations of the invention ingredient can be prepared as an admixture or other pharmaceutical formulation to be applied in a wide variety of 130 ways including, but are not limited to, lotions, creams gels, sticks, sprays, ointments and pastes. These product types may comprise several types of formulations including, but not limited to solutions, emulsions, gels, solids, and liposomes. If the topical composition of the invention is formulated as an aerosol and applied to the skin as a spray-on, a propellant may be added to a solution composition. Suitable propellants as used in the art can be utilized.
  • topical administration of an active agent reference is made to U.S.
  • Carriers or excipients can also be used to facilitate administration of the compositions and formulations of the invention.
  • carriers and excipients include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, polyethylene glycols and physiologically compatible solvents.
  • a stabilizer may be included in the formulations of the invention, but will generally not be needed. If included, however, a stabilizer useful in the practice of the invention is a carbohydrate or a polyhydric alcohol.
  • a therapeutically effective amount of pre-complexed copper antagonist is an amount capable of providing an appropriate level of pre-complexed copper antagonist in the bloodstream. By increasing the bioavailability of pre- complexed copper antagonist, a therapeutically effective level of pre-complexed copper antagonist may be achieved by administering lower dosages than would otherwise be necessary.
  • Copper antagonists other than triethylenetetramine dihydrochloride or triethylenetetramine disuccinate may be used, as may sources of non-copper metal ions other than Zn 2+ (e.g., sources of Ca 2+ , Mg 2+ , Cr 2+ , Cr 3+ , Mn 2+ , Se 4+ , Fe 2+ , Fe 3+ ,
  • sources of non-copper metal ions other than Zn 2+ e.g., sources of Ca 2+ , Mg 2+ , Cr 2+ , Cr 3+ , Mn 2+ , Se 4+ , Fe 2+ , Fe 3+ ,
  • Amounts of the pre- complexed copper antagonist(s), including the amounts of pre-complexed triethylenetetramine dihydrochloride or pre-complexed triethylenetetramine disuccinate and the non-copper metal ion set forth in this Example, may be varied, as appropriate.
  • the product is then dried on a rotary evaporator.
  • the process employs a combination of blending and direct encapsulation techniques.
  • the pre-complexed copper antagonist is blended, for example, with lactose in a suitable blender.
  • suitable blenders include, for example, v-blenders (Patterson- Kelly), and planetary blenders (Hobart Corp).
  • the resulting blend is mixed with the crosscarmellose sodium in the same blender. This blend may be milled and screened in a Fitz mill (Fitzpatrick Corp) or other suitable mill, such as a Quadro Comill, oscillating mill, or pin mill, for example.
  • the resulting blend is mixed with the magnesium stearate, or other lubricant, which may also be accomplished in a suitable blender.
  • the amount of pre-complexed triethylenetetramine dihydrochloride or pre-complexed triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, and about 750 mg, or any amount in between any of these amounts). Other amounts may also be used. The amounts are not inflexible 173 and may be determined, in part, for example, based on the number of tablets to be taken per day.
  • the process employs compaction and direct compression.
  • the pre-complexed copper antagonist(s) is/are first compacted, for example, in a suitable roller compacter.
  • Suitable roller compactors include, for example, the Vector Mini-Model TF (Vector Corp., Marion, IA). It is then milled with a Fitz mill (Fitzpatrick Company, Elmhurst, 111.) or other suitable mill, such as a Comill mill, oscillator mill, or pin mill, for example. 175
  • the milled pre-complexed copper antagonist is blended with hydroxypropyl- methylcellulose, and lactose in a suitable blender.
  • Suitable blenders include V- Blenders (Patterson-Kelly, and planetary blenders (Hobart Corp., Troy OH.). This blend is blended with the magnesium stearate or other lubricant in the same blender.
  • the amount of pre-complexed triethylenetetramine dihydrochloride or pre-complexed triethylenetetramine disuccinate may range from about 1 mg to about 750 mg (for example, about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, and about 750 mg, or any amount in between any of these amounts).

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Abstract

L’invention se rapporte à des compositions pharmaceutiques ayant un composé antagoniste du cuivre pharmaceutiquement acceptable, par exemple des antagonistes du cuivre (II), complexés à un ion métallique exempt de cuivre pharmaceutiquement acceptable, des articles, des kits et des dispositifs de délivrance contenant ces compositions, des comprimés, des gélules et des formulations contenant ces compositions, ainsi que des procédés d’utilisation pour le traitement de sujets, y compris d’humains, qui sont atteints de nombreuses maladies, troubles et états pathologiques ou sont exposés à un risque vis-à-vis de ceux-ci.
PCT/NZ2006/000053 2005-03-26 2006-03-27 Compositions antagonistes du cuivre pre-complexees WO2006104396A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1877801A1 (fr) * 2005-04-25 2008-01-16 Protemix Corporation Limited Thérapie et évaluation de la régulation par l'utilisation du cuivre
WO2012096839A1 (fr) * 2011-01-11 2012-07-19 Jr Chem, Llc Compositions à usage ano-rectal et méthodes de traitement de troubles ano-rectaux
WO2022187709A1 (fr) * 2021-03-05 2022-09-09 Philera New Zealand Traitement de troubles liés au cuivre

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017522A1 (fr) * 1999-09-08 2001-03-15 Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center Procede de traitement du cancer par utilisation de disulfure de tetraethylthiurame
WO2003051348A2 (fr) * 2001-12-18 2003-06-26 Murphy Michael A Composition, synthese et applications therapeutiques de polyamines
WO2003057176A2 (fr) * 2002-01-08 2003-07-17 Emory University Porphyrines a activite virucide
WO2004080481A1 (fr) * 2003-03-13 2004-09-23 Novo Nordisk A/S Nouvelles preparations d'insuline nph
WO2004084799A2 (fr) * 2003-03-27 2004-10-07 Jerachmiel Appelbaum Compositions pharmaceutiques destinees a inhiber l'activite enzymatique dependante des ions metalliques et techniques d'utilisation de celles-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001017522A1 (fr) * 1999-09-08 2001-03-15 Charlotte-Mecklenburg Hospital Authority Doing Business As Carolinas Medical Center Procede de traitement du cancer par utilisation de disulfure de tetraethylthiurame
WO2003051348A2 (fr) * 2001-12-18 2003-06-26 Murphy Michael A Composition, synthese et applications therapeutiques de polyamines
WO2003057176A2 (fr) * 2002-01-08 2003-07-17 Emory University Porphyrines a activite virucide
WO2004080481A1 (fr) * 2003-03-13 2004-09-23 Novo Nordisk A/S Nouvelles preparations d'insuline nph
WO2004084799A2 (fr) * 2003-03-27 2004-10-07 Jerachmiel Appelbaum Compositions pharmaceutiques destinees a inhiber l'activite enzymatique dependante des ions metalliques et techniques d'utilisation de celles-ci

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FOYE W. ET AL.: "Chelation of Beta-phenethylbiguanide and Other Biguanides with Copper Ion", J PHARMACEUTICAL SCIENCES, vol. 50, no. 8, 1961, pages 641 - 644 *
MEHRA A. ET AL.: "Selective Cleavage of N-terminal amino acid in a peptide by polymeric cobalt(III) triene complex", INDIAN J BIOCHEM & BIOPHYSICS, vol. 26, 1989, pages 348 - 349 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1877801A1 (fr) * 2005-04-25 2008-01-16 Protemix Corporation Limited Thérapie et évaluation de la régulation par l'utilisation du cuivre
EP1877801A4 (fr) * 2005-04-25 2009-03-18 Protemix Corp Ltd Thérapie et évaluation de la régulation par l'utilisation du cuivre
WO2012096839A1 (fr) * 2011-01-11 2012-07-19 Jr Chem, Llc Compositions à usage ano-rectal et méthodes de traitement de troubles ano-rectaux
US8952057B2 (en) 2011-01-11 2015-02-10 Jr Chem, Llc Compositions for anorectal use and methods for treating anorectal disorders
WO2022187709A1 (fr) * 2021-03-05 2022-09-09 Philera New Zealand Traitement de troubles liés au cuivre

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