WO2008153967A1 - Conjugués antagonistes de bk1 - Google Patents

Conjugués antagonistes de bk1 Download PDF

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Publication number
WO2008153967A1
WO2008153967A1 PCT/US2008/007157 US2008007157W WO2008153967A1 WO 2008153967 A1 WO2008153967 A1 WO 2008153967A1 US 2008007157 W US2008007157 W US 2008007157W WO 2008153967 A1 WO2008153967 A1 WO 2008153967A1
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substituted
covalent bond
alkyl
independently
moiety
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PCT/US2008/007157
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English (en)
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Michael A. Pleiss
Stephen B. Freedman
Hans Allgeier
Gisela Peraus
Gabriele Stumm
Klaus Dembowsky
Michael C. Nehls
Martin Augustin
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Contec Therapeutics, Inc.
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Publication of WO2008153967A1 publication Critical patent/WO2008153967A1/fr

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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
    • A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention relates to conjugated Bradykinin-1 (BK1) ligands, specifically BK1 antagonists, methods of their production and uses thereof.
  • BK1 ligands and antagonists, according to the invention are conjugated with a biocompatible polymer, such as PEG.
  • Conjugated BK1 antagonists are useful for treating those diseases mediated by the BK1 receptor, including but not limited to in the treatment of various diseases, including inflammatory diseases and pain.
  • Covalent attachment of BK1 ligands or antagonists to biocompatible polymers is a highly advantageous method of increasing water solubility and bioavailability and extending the circulation time of many biologically active molecules, particularly hydrophobic molecules.
  • biocompatible polymers such as the hydrophilic polymer poly(ethylene glycol), abbreviated PEG, or other biocompatible polymer
  • PEG poly(ethylene glycol)
  • PEG poly(ethylene glycol)
  • the total molecular weight of the polymer or polymers attached to the biologically active molecule must be sufficiently high to impart the advantageous characteristics typically associated with PEG polymer attachment, such as increased water solubility and circulating half life, while not adversely impacting the bioactivity of the parent molecule.
  • Covalent attachment of BK1 ligands or antagonists to biocompatible polymers is a highly advantageous method of increasing water solubility and bioavailability and extending the circulation time of many biologically active molecules, particularly hydrophobic molecules.
  • the total molecular weight of the polymer or polymers attached to the biologically active molecule must be sufficiently high to impart the advantageous characteristics typically associated with PEG polymer attachment, such as increased water solubility and circulating half life, while not adversely impacting the bioactivity of the parent molecule.
  • Covalent attachment of a biocompatible polymer such as PEG to a protein has been used to improve the circulating half-life, decrease immunogenicity, and/or reduce proteolytic degradation.
  • Proteins for injection that are modified by covalent attachment of PEGs are typically modified by attachment of relatively high molecular weight PEG polymers that often range from about 5,000 to about 40,000 Daltons.
  • Pegylation has also been used, albeit to a limited degree, to improve the bioavailability and ease of formulation of small molecule drugs having poor aqueous solubilities.
  • water-soluble polymers such as PEG have been covalently attached to artilinic acid to improve its aqueous solubility.
  • PEG has been covalently attached to triazine-based compounds such as trimelamol to improve their solubility in water and enhance their chemical stability. See, for example, International Patent Publication WO 02/043772.
  • PEG chains attached to small molecule drugs for the purpose of increasing their aqueous solubility are typically of sizes ranging from: about 500 Daltons to about 5000 Daltons, depending upon the molecular weight of the small molecule drug.
  • WO05/058367 discloses composition comprised of monodisperse or bimodal conjugates, each conjugate comprising a moiety derived from a small molecule drug covalently attached by a stable linkage to a water- soluble polymer.
  • the polymer is obtained from a monodisperse (i.e., unimolecular) composition.
  • US 2005/0238614 and US 2006/0013799 discloses conjugate compounds in which a
  • VLA-4 binding small molecule is conjugated with a PEG polymer.
  • PEG polymer conjugated with a PEG polymer.
  • conjugate compounds can be used to treat various diseases.
  • a conjugate of a BK1 antagonist with a biocompatible polymer is not disclosed.
  • Bradykinin or kinin-9 is a kinin that plays an important role in the patho- physiological processes accompanying acute and chronic pain and inflammation.
  • BKs like other related kinins, are autocoid peptides produced by the catalytic action of kallikrein enzymes on plasma and tissue precursors termed kininogens.
  • BK is a vaso-active nine-amino acid peptide (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) that is formed locally in body fluids and tissues from the plasma precursor kininogen during inflammatory processes. It is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. BK is also known to be one of the most potent naturally occurring stimulators of C-fiber afferents mediating pain, and a physiologically active component of the kallikrein-kinin system. BK is released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter.
  • BK is also a powerful blood-vessel dilator, increasing vascular permeability and causing a fall in blood pressure, an edema-producing agent, and a stimulator of various vascular and non-vascular smooth muscles in tissues such as uterus, gut and bronchiole. BK is formed in a variety of inflammatory conditions and in experimental anaphylactic shock.
  • the kinin/kininogen activation pathway has also been described as playing a pivotal role in a variety of physiologic and pathophysiologic processes, being one of the first systems to be activated in the inflammatory response and one of the most potent simulators of: (i) phospholipase A2 and, hence, the generation of prostaglandins and leukotrienes; and (ii) phospholipase C, and thus, the release of inositol phosphates and diacylgylcerol. These effects are mediated predominantly via activation of BK receptors of the BK2 type.
  • a BK receptor is any membrane protein that binds BK and mediates its intracellular effects.
  • Two recognized types of receptors are BK1 and BK2.
  • BK1 receptors are considerably less common than BK2 receptors, which are present in most tissues.
  • the rat BK2 receptor is a seven-transmembrane-domain protein that has been shown on activation to stimulate phosphoinositide turnover. Inflammatory processes induce the BK1 subtype. See, e.g., Marceau, Kinin B1 Receptors: A Review, Immunopharmacology, 30:1-26 (1995).
  • receptor BK1 The distribution of receptor BK1 is very limited since this receptor is only expressed during states of inflammation.
  • receptors human
  • BK1 database code BRB1_HUMAN, 353 amino acids (40.00 kDa); and BK2, database code BRB2JHUMAN, 364 amino acids (41.44 kDa).
  • BK Binding-like materials
  • BK receptors have been localized to nociceptive peripheral nerve pathways and BK has been demonstrated to stimulate central fibers mediating pain sensation.
  • BK has also been shown to be capable of causing hyperalgesia in animal models of pain.
  • BK antagonists offer a highly desirable alternative approach to the therapy of migraine.
  • BK is produced during tissue injury and can be found in coronary sinus blood after experimental occlusion of the coronary arteries.
  • BK when directly injected into the peritoneal cavity, BK produces a visceral type of pain.
  • a visceral type of pain See, e.g., Ness, et al., Visceral pain: a Review of Experimental Studies, Pain, 41:167-234 (1990). While multiple other mediators are also clearly involved in the production of pain and hyperalgesia in settings other than those described above, it is also believed that antagonists of BK have a place in the alleviation of such forms of pain as well.
  • BK antagonists have also been shown to reduce cerebral edema in animals after brain trauma. Based on the above, it is believed that BK antagonists should be useful in the management of stroke and head trauma.
  • BK receptors are present in the lung, that BK can cause bronchoconstriction in both animals and man, and that a heightened sensitivity to the bronchoconstrictive effect of BK is present in asthmatics.
  • Some studies have been able to demonstrate inhibition of both BK and allergen-induced bronchoconstriction in animal models using BK antagonists. These studies indicate a potential role for the use of BK antagonists as clinical agents in the treatment of asthma. See, e.g., Barnes, Inflammatory Mediator Receptors and Asthma, Am. Rev. Respir. Dis., 135:S26-S31 (1987).
  • BK antagonists as analgesics.
  • a number of studies have demonstrated that BK antagonists are capable of blocking or ameliorating both pain as well as hyperalgesia in mammals including humans. See, e.g., Ammons, W. S., et al., Effects of Intracardiac Bradykinin on T2-
  • BK antagonists Prior efforts in the field of BK antagonists indicate that such antagonists can be useful in a variety of roles. These include use in the treatment of burns, perioperative pain, migraine and other forms of pain, shock, central nervous system injury, asthma, rhinitis, premature labor, inflammatory arthritis, inflammatory bowel disease, neuropathic pain, etc.
  • LF22-0542 and its synthesis is known from French patent FR2840897 from Fournier. Fournier has described related BK1 antagonists in FR2852958 and WO 2004/087700. Extensive in vitro and in vivo (pain and inflammation) profiling is described in Porreca and coworkers, J. Pharmacol. Exp. Ther. 2006, 318, 195-205. Sevcik and coworkers, J. of Pain 2005, 6(11 ), 771-775 describe the use of LF22-0542 in a bone cancer pain model.
  • SSR240612 is well a well known BK1 antagonist, whose preparation is described in WO 2002/076964 from Sanofi. Gougat and coworkers in J. Pharmacol. Exp. Ther. 2004, 309, 661-669 describe in vitro and in vivo evaluation of SSR240612.
  • ELN441958 one further well known BK1 antagonsit. It is known from WO06/113140 and US 2007/0032475. In vitro and in vivo profiling has been presented by Hawkinson and coworkers, Society of Neuroscience Abstracts, 2006, 36th Annual Meeting, Atlanta, GA, Poster 49.11. Pharmacokinetic and pharmacology of ELN441958 is described by Hawkinson and coworkers, J. Pharmacol. Exp. Ther. 2007, (fast forward article: DOI: 10.1124/jpet.107.120352).
  • NVP-SAA164 Synthesis and pharmacokinetics of NVP-SAA164 is described in Ritchie and coworkers, J. Med. Chem. 2004, 47(19), 4642-4644. Evaluation in a humanized transgenic mouse model is described in Fox and coworkers, Brit. J. Pharmacol. 2005, 144(7), 889-899. Synthesis and evaluation of Amgen compound 28 is described in D'Amico and coworkers, J. Med. Chem. 2007, 50, 607-610.
  • R-892 BK1 antagonistic peptide having the structure:
  • the present invention relates to modified BK1 antagonists.
  • Modified antagonists of the invention are conjugates of a small molecule BK1 antagonist and a water-soluble biocompatible polymer, such as polyethylene glycol (PEG) separated by a linker.
  • the conjugated BK1 antagonists described in this invention are comprised of an active small molecule BK1 antagonist which is covalently attached to a linker.
  • the linker placement is crucial for several reasons: (1) the linker serves as a neutral spacer between the active small molecule BK1 antagonist and the biocompatible polymer; and (2) attachment of the linker to the small molecule BK1 antagonist must be such that the potency of the small molecule antagonist is maintained (see, "Design and Placement of Linkers for BK1 antagonist conjugates") for a description of how this is accomplished.
  • the present invention also relates to methods of preparing conjugates of the invention, as well as to methods of administering such conjugates to patients in need.
  • the present invention furthermore relates to pharmaceutical preparations comprising conjugates of the invention and at least one pharmaceutically acceptable excipient.
  • the present invention also relates to methods of preparing pharmaceutical compositions of the invention.
  • the water-soluble biocompatible polymer when attached to the small molecule drug, effectively diminishes the ability of the resulting conjugate to cross certain biological membranes, such as those associated with the blood-brain barrier or the blood-placental barrier.
  • a conjugate is provided that exhibits a reduced biological membrane crossing rate as compared to the biological membrane crossing rate of the small molecule drug not attached to the water-soluble biocompatible polymer.
  • BK1 antagonist conjugates of the present invention show an improved bioavailability as compared to the respective small molecule BK1 antagonists in their non-conjugated form.
  • Conjugates of the invention can advantageously alter certain properties associated with the corresponding small molecule drug.
  • a conjugate of the invention when administered by any of a number of suitable administration routes, such as parenteral, oral, transdermal, buccal, pulmonary, or nasal, exhibits reduced penetration across a biological membrane (such as the biological membranes associated with the blood-brain barrier and blood-placental barrier). It is preferred that the conjugates exhibit slowed, minimal or effectively non-crossing of biological membranes (such as the biological membranes associated with the blood-brain barrier and blood-pfacental barrier), white still crossing the gastro-intestinal walls and into the systemic circulation if oral delivery is intended.
  • the conjugate administered will preferably have no crossing into systemic circulation or a reduced pulmonary tissue-blood barrier crossing rate so that local lung levels are maintained for local pharmacologic activity in the lung. Moreover, the conjugates of the invention maintain a degree of bioactivity as well as bioavailability in their conjugated form. Administration of the conjugates of the invention exhibits a reduction in first pass metabolism as compared to the corresponding small molecule drug in its un-conjugated form.
  • the invention provides for a method for reducing the metabolism and/or elimination of an active agent, the method comprising the steps of: providing conjugates of the invention, each conjugate comprised of a moiety derived from a small molecule drug covalently attached by a stable linkage to a water-soluble biocompatible polymer, wherein said conjugate exhibits a reduced rate of metabolism and/or elimination as compared to the rate of metabolism and/or elimination of the small molecule drug not attached to the water- soluble polymer; and administering said conjugate to a patient.
  • Figure 1 shows a comparison of the therapeutic effect of a small molecule (Compound A) with its linker conjugate (Compound B).
  • Figure 2 shows a comparison of the therapeutic effect of a small molecule (Compound A) with its PEG-linker conjugate (Compound C).
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)- , substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)- cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloa!kyl-C(O)O-, substituted cyc!oalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted
  • Alkenyl refers to alkenyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of alkenyl unsaturation. Such groups are exemplified by vinyl, allyl, but-3-en-1-yl, and the like.
  • Alkoxy refers to an -O-R group, wherein R is alkyl or substituted alkyl, preferably C1-C20 alkyl (e.g., methoxy, ethoxy, propy/oxy, benzyl, etc.), preferably C1-C7.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 5 carbon atoms and more preferably 1 to 3 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.
  • Alkylene refers to divalent saturated aliphatic hydrocarbyl groups preferably having from 1 to 5 and more preferably 1 to 3 carbon atoms which are either straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (- CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-) and the like.
  • Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy and the like.
  • Alkynyl refers to alkynyl groups having from 2 to 6 carbon atoms and preferably 2 to
  • Amino refers to the group -NH2.
  • Aminoacyl refers to the group -C(O)NR 10 R 10 where each R 10 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R 10 is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2- benzoxazolinone, 2H- 1
  • aryls include phenyl and naphthyl.
  • Aryloxy refers to the group aryl-O- that includes, by way of example, phenoxy, naphthoxy, and the like.
  • Biocompatible polymer refers generally to a polymer that is tolerated when placed within the body without causing significant adverse reactions (e.g., toxic or antigenic responses).
  • the biocompatible polymer is non-immunogenic.
  • the biocompatible polymer is water soluble.
  • suitable polymers include, but are not limited to: polyoxyalkylene polymers such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyacrylamide (PAAm), polydimethylacrylamide (PDAAm), polyvinyl alcohol (PVA), dextran, poly (L-glutamic acid) (PGA), styrene maleic anhydride (SMA), poly-N-(2- hydroxypropyl) methacrylamide (HPMA), polydivnylether maleic anhydride (DIVEMA) (Kameda, Y. et al., Biomaterials 25: 3259-3266, 2004; Thanou, M.
  • PEG polyethylene glycol
  • PVP polyvinylpyrrolidone
  • PAAm polyacrylamide
  • PDAAm polydimethylacrylamide
  • PVA polyvinyl alcohol
  • DEMA poly (L-glutamic acid)
  • SMA styrene maleic anhydride
  • HPMA poly-N-(
  • Preferred polymers are polyoxyalkylenes.
  • polyoxyalkylenes macromolecules that include at least one polyalkylene oxide portion that is optionally covalently bonded to one or more additional polyakylene oxides, wherein the polyalkylene oxides are the same or different.
  • Non-limiting examples include polyethylene glycol (PEG), polypropylene glycol (PPG), polyisopropylene glycol (PIPG), PEG-PEG, PEG-PPG 1 PPG- PIPG, and the like.
  • macromolecules wherein the polyalkylene oxide portions are optionally connected to each other by a linker.
  • Illustrative examples are PEG-linker-PEG, PEG-linker-PIPG, and the like.
  • More specific examples include the commercially available poly[di(ethylene glycol)adipates], poly[di(ethylene glycol)phthalate diols], and the like.
  • Other examples are block copolymers of oxyalkylene, polyethylene glycol, polypropylene glycol, and polyoxyethylenated polyol units.
  • Bio membrane crossing rate refers to a measure of a compound's ability to cross a biological barrier, such as the blood-brain barrier (“BBB").
  • BBB blood-brain barrier
  • a variety of methods can be used to assess transport of a molecule across any given biological membrane. Methods to assess the biological membrane crossing rate associated with any given biological barrier (e.g., the blood- cerebrospinal fluid barrier, the blood-placental barrier, the blood-milk barrier, the intestinal barrier, and so forth), are known, described herein and/or in the relevant literature, and/or can be determined by one of ordinary skill in the art.
  • Biological membrane refers to any membrane, typically made from specialized cells or tissues, that serves as a barrier to at least some xenobiotics or otherwise undesirable materials.
  • biological membrane includes those membranes that are associated with physiological protective barriers including, for example: the blood-brain barrier; the blood-cerebrospinal fluid barrier; the blood- placental barrier; the blood-milk barrier; the blood-testes barrier; and mucosal barriers including the vaginal mucosa, urethral mucosa, anal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa, and so forth). Unless the context cleariy dictates otherwise, the term “biological membrane” does not include those membranes associated with the middle gastro-intestinal tract (e.g., stomach and small intestines).
  • BK1 Antagonist is a "BK1 Ligand” that demonstrates an (C50 within 5000-fold relative to [des-Arg 10 ]-HOE140 in a relevant BK1 assay (i.e. a BK1 antagonist, according to the invention, may be an up to 5000 fold less potent BK1 inhibitor than [des-Arg 10 ]-HOE140).
  • a BK1 antagonist shows an IC50 of at most 25 ⁇ M in the cell based (human HS-729 rhabdomyosarcoma (fibroblast) cells) as run by NovaScreen [Cat #: 300-0283] (Hanover, Maryland, USA) [www.novascreen.com], if the potent BK1 antagonist [des-Arg 1& ]- HOE 140 (CAS No. 138680-92-9; available from Sigma, Cat. No. H 158 or AnaSpec (San Jose, CA, USA) Cat. No. 22970) is 5 nM in this assay. A description of the assay can be found in the examples.
  • BK-1 Ligand is a small molecule, peptide, nucleotide or aptomer (or others e.g., lipids, glycoprotein, etc.) that binds to or directly interacts with the human bradykinin BK-1 receptor resulting in either blockade, occupancy or partial activation of the receptor. This interaction could be at either the competitive binding site where traditional previously described BK-1 ligands interact or any additional sites which result in loss of function of the receptor. Activity can be demonstrated by either (but not limited to) radioligand binding assays or functional assays of BK-1 receptor function.
  • Carboxyl ester refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)- aryl, and -C(O)O-SU bstituted aryl wherein alkyl, substituted alkyl, aryl and substituted aryl are as defined herein.
  • Carboxyl refers to -COOH or salts thereof.
  • Crossing the blood-brain barrier in accordance with the invention, means crossing of the blood-brain barrier at a rate greater than that of atenolol using methods that can be determined by one of ordinary skill in the art.
  • compound and “active compound” are used to refer to the BK1 antagonist portion of the conjugate of the invention or to a BK1 antagonist as it exists prior to conjugation to a polymer.
  • Cyano refers to the group -CN.
  • Cycloalkoxy refers to -O-cycloalkyl groups.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including, by way of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • Halogenated alkyl refers alkyl which is halogenated at one or several positions.
  • Heteroaryl refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring.
  • heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothie ⁇ yl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group.
  • Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • Heteroaryloxy refers to the group -O-heteroaryl and "substituted heteroaryloxy” refers to the group -O-substituted heteroaryl.
  • Heterocycle or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be cycloalkyl, aryl or heteroaryl provided that the point of attachment is through the heterocyclic ring.
  • Heterocyclyloxy refers to the group heterocyclyl-O- and "substituted heterocyclyl-O-” refers to the group substituted heterocyclyl-O- where heterocyclyl and substituted heterocyclyl are as defined above.
  • Hydrolyzable ester refers to a group that is hydrolyzed in vivo to produce the the parent acid. Examples of such groups include alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy and substituted aryloxy. A preferred hydrolyzable ester is alkoxy.
  • Hydrolyzable polymer ester refers to a biocompatible polymer that is hydrolyzed in vivo to produce the parent acid. A preferred hydrolyzable polymer ester is PEG.
  • Haldroxy refers to the group -OH.
  • Immunological disease as used herein, relates to the normal meaning of this term. Immunological diseases include, but are not limited to, allergy, asthma, graft-versus-host disease, immune deficiencies and autoimmune diseases.
  • a “linker”, within the meaning of the patent is any can be any suitable linkage to bind molecules, although a covalent linkage is preferred. Suitable covalent linkages between the water-soluble polymer and the small molecule drug comprise, without limitation, the following: ether; amide; urethane; amine; thioether; and a carbon-carbon bond.
  • the linker or linkage of the invention may be a single atom, such as an oxygen or a sulfur, two atoms, or a number of atoms.
  • a linker is typically but is not necessarily linear in nature.
  • the linker, "L”, is hydrolytically stable, and is preferably also enzymatically stable.
  • the linker is one having a chain length of 1 to 100, preferably 4 to 60, more preferably 5 to 20 atoms.
  • the linker "L” is hydrolytically stable and comprises an ether, amide, urethane, amine, thioether, urea, or a carbon- carbon, bond.
  • a linker of the invention can be a comparatively short linker, which may be any of the following: -0-, -NH-, -S-, -C(O)-, -C(O)- NH, NH-C(O)-NH, -0-C(O)-NH-, -C(S)-, -CH2-, -CH2-CH2-, -CH2- CH2-CH2-, -CH2-CH2- CH2-CH2-, -O-CH2-, -CH2-O-, -0-CH 2 -CH 2 -, -CH 2 -O-CH 2 -, -CH 2 -CH 2 -O-, -0-CH 2 -CH 2 -CH 2 -,- CH 2 "O-CH 2 "CH 2 ⁇ ,”CH 2 "Cri 2 *O ⁇ CH 2 ⁇ , ⁇ CH 2 "CH 2 ⁇ Crl2"O", -O-CH 2 ⁇ CH 2 "CH2 ⁇ Cn 2 ⁇ , -GH 2
  • Linkers are those defined in the claims.
  • “Lower alkyl” refers to an alkyl group containing from 1 to 6 carbon atoms, and may be straight chain or branched, as exemplified by methyl, ethyl, n-butyl, i-butyl, t-butyl.
  • “Lower alkoxy” within this context, means C1 to C40 alkoxy, more preferably C1 to C20 alkoxy, more preferably C1 to C10 alkoxy, more preferably C1 to C6 alkoxy, C1 to C4 alkoxy, most preferred methoxy.
  • Niro refers to the group -NO2.
  • Optionally substituted alkyl encompasses “alkyl” and “substituted alkyl” as defined above.
  • Optionally substituted -CH2- refers to a group that is either unsubstituted or is substituted with 1 or 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, thioalkoxy, substituted thioalkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, sulfhydryl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, spirocycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • substituents on "optionally substituted -CH 2 -" are hydroxy, alkoxy, amino, monoalkyl amino, dialkylamino, sulfhydryl, thioalkoxy, and halogen (preferably F).
  • halogen preferably F
  • Orally bioavailable relates to the property of a compound (such as a small molecule drug or conjugate thereof) that that possesses a bioavailability when administered orally of greater than 1%, and preferably greater than 5%, more preferably more than 10%, wherein a compound's bioavailability is the fraction of administered drug that reaches the systemic circulation in un-metabolized form.
  • Parenter injection means subcutaneous, intravenous, intra-arterial, intraperitoneal, intracardiac, intrathecal, or intramuscular injection.
  • Patient refers to a living organism suffering from or prone to a condition that can be prevented or treated by administration of a conjugate as described herein.
  • a patient can be human or can be an animals. Human patients are preferred.
  • PEG polyethylene glycol
  • polyethylene glycol is meant to encompass any water- soluble poly(ethylene oxide). Unless otherwise indicated, a "PEG polymer” or a polyethylene glycol is one in which all of the monomer subunits are ethylene oxide subunits. Typically, substantially all, or all, monomeric subunits are ethylene oxide subunits, -though the polymer may contain distinct end capping moieties or functional groups, e.g. for conjugation.
  • PEG-polymers for use in the present invention will comprise one of the two following structures: "-(CH 2 CH 2 O) n -" or “-(CH 2 CH 2 O) n -CH 2 CH 2 -,” depending upon whether or not the terminal oxygen(s) has been displaced, e.g., during a synthetic transformation.
  • the variable (n) ranges from 4 to 2000, preferably 40-1000, more preferably 90-600.
  • PEG further comprises a functional group, A, for linking to, e.g., a small molecule drug
  • the functional group when covalently attached to a PEG polymer preferably does not result in formation of (i) an oxygen-oxygen bond (-O-O-, a peroxide linkage), or (ii) a nitrogen-oxygen bond (N-O, O-N).
  • Protein as used herein, is meant to encompass a chain of amino acids connected by amide bonds.
  • An amino acid has a carboxylic acid group and an amino group separated by at least one methylene group and up to four methylenes.
  • the methylenes may be substituted with one or more moieties, including disubstitution on the same methylene and/or differing methylenes.
  • the moieties are selected from the list consisting of alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, cycloalkenyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, heterocyclic, substituted heterocyclic, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, heterocycloxy,
  • the moieties may be chiral.
  • the terminal amino group of the peptide may be substituted by a moiety selected from the list consisting of hydrogen, alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, acyl, ami ⁇ oacy/, acyloxy, alkenyl, substituted alkenyJ, aryl, substituted aryl, cycloalkyl, cycloalkenyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic.
  • the terminal carboxylic acid group of the peptide may be substituted by a moiety selected from the list consisting of hydrogen, alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, cycloalkenyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, heterocyclic, substituted heterocyclic, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thiohe
  • “Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to an excipient that can be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient.
  • Reduced rate of metabolism refers to a measurable reduction in the rate of metabolism of a conjugate of the invention as compared to rate of metabolism of the small molecule drug not attached to the biocompatible polymer (i.e., the small molecule drug itself) or a reference standard material.
  • reduced first pass rate of metabolism the same “reduced rate of metabolism” is required except that the small molecule drug (or reference standard material) and the corresponding conjugate are administered by the same route of administration. Because the liver is the primary site of drug metabolism or biotransformation, a substantial amount of drug can be metabolized before it ever reaches the systemic circulation. The degree of first pass metabolism, and thus, any reduction thereof, can be measured by a number of different approaches.
  • a conjugate of the invention can provide a reduced rate of metabolism reduction satisfying at least one of the following values: at least about 5%, at least about 10%, at least about 15%; least about 20%; at least about 25%; at least about 30%; at least about 40%; at least about 50%; at least about 60%; at least about 70%; at least about 80%; and at least about 90%.
  • Small molecule refers to an organic, inorganic, or organometallic compound having a molecular weight of less than 1000 Da.
  • substantially or “essentially”, within the context of the present invention, means nearly totally or completely, for instance, 95% or greater, more preferably 97% or greater, still more preferably 98% or greater, even more preferably 99% or greater, yet still more preferably 99.9% or greater, with 99.99% or greater being most preferred of some given quantity.
  • Substituted a/kenyl refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that any hydroxyl substitution is not attached to a vinyl (unsaturated) carbon atom.
  • Substituted alkoxy refers to the group “substituted alkyl-O-”.
  • Substituted alkyl refers to an alkyl group having from 1 to 3, and preferably 1 to 2, substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, spirocycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.
  • Substituted amino refers to the group -NR 1 R" where R 1 and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R 1 and R" are joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group provided that R 1 and R" are both not hydrogen.
  • R' is hydrogen and R" is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R' and R" are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R" or R" is hydrogen but not both.
  • a disubstituted amino it is meant that neither R' or R" is hydrogen.
  • Substituted aryl refers to aryl groups which are substituted with from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of hydroxy, acyl, acylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, carboxyl, carboxyl esters, cyano, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substituted thi
  • Substituted aryloxy refers to substituted aryl-O- groups.
  • Substituted cycloalkoxy refers to -O-substituted cycloalkyl groups.
  • Substituted heteroaryl refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl.
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • heterocyclyls and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 ,2,3,4-tetrahydro-isoquinoline
  • Substituted thioaryl refers to the group -S-substituted aryl, where substituted aryl is defined above.
  • Thioheteroaryl refers to the group -S-heteroaryl, where heteroaryl is as defined above.
  • Substituted thioheteroaryl refers to the group -S-substituted heteroaryl, where substituted heteroaryl is defined above.
  • Thioalkyl or “alkylthioether” or “thioalkoxyl” refers to the group -S-alkyl.
  • Thioaryl refers to the group -S-aryl, where aryl is defined above.
  • Thiocycloalkyl refers to the group -S-cycloalkyl and "substituted thiocycloalkyl” refers to the group -S-substituted cycloalkyl, where cycloalkyl and substituted cycloalkyl are as defined above.
  • Thioheterocyclic refers to the group -S-heterocyclic and "substituted thioheterocyclic” refers to the group -S-substituted heterocyclic, where heterocyclic and substituted heterocyclic.
  • Thiol refers to the group -SH.
  • the current invention relates to a conjugate compound of the formula I:
  • A is a BK1 ligand covalently bound to L, n is 1 , 2, 3, 4, or an integer greater than 4;
  • L is a linker covalently bound to said biocompatible polymer, said linker having the structure "X-NR 1 R 2 , wherein
  • R 1 is hydrogen or lower alkyl
  • R 2 is
  • R 3 and R 4 are independently of each other hydrogen, alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, acyl, aminoacyl, acyloxy, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic,
  • R 5 is a moiety selected from the list consisting of alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyf, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, cycloalkenyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, heterocyclic, substituted heterocyclic, thiol, thioaJkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, hetero
  • the invention also relates to conjugate compounds as defined above, wherein A is a BK1 antagonist.
  • A is a BK1 antagonist demonstrating an activity within 1000-fold relative to [des-Arg 10 ]-HOE140 in a relevant BK1 assay, more preferably within 500-fold, or 100-fold, most preferably within 50-fold relative to [des-Arg 10 ]-HOE140 in a relevant BK1 assay.
  • A is a BK1 antagonist demonstrating an IC50 value of less than 25 ⁇ M, preferably less than 10 ⁇ M, more preferably less than 1 ⁇ M, more preferably less than 100 nM, more preferably less than 10 nM, most preferred less than 5 nM, as determined by a relevant BK1 assay, as disclosed in the examples section.
  • the conjugate is a BK1 antagonist demonstrating an activity within 1000-fold relative to [des-Arg 10 ]-HOE140 in a relevant BK1 assay, more preferably within 500-fold, or 100-fold, most preferably within 50-fold relative to [des-Arg 10 ]-HOE140 in a relevant BK1 assay.
  • the conjugate is a BK1 antagonist demonstrating an IC50 value of less than 25 ⁇ M, preferably less than 10 ⁇ M, more preferably less than 1 ⁇ M, more preferably less than 100 nM, more preferably less than 10 nM, most preferred less than 5 nM, as determined by a relevant BK1 assay, as disclosed in the examples section.
  • conjugate compounds of the invention A is a small molecule.
  • conjugate compounds of the invention A is a peptide.
  • said biocompatible polymer is PEG.
  • Preferred PEGs of the invention are selected from the list consisting of
  • Preferred PEGs of the invention are SUNBRIGHT ME-200HS (MW 20.000), SUNBRIGHT DE-200HS (MW 20.000), SUNBRIGHT PTE-200HS (MW 20.000) all available from NOF America Corporation (White Plains, U.S.A.)
  • the biocompatible polymer has an average molecular weight of 2000 to 40000 kDa.
  • L is selected from the group consisting of
  • compound A in a conjugate compound defined above, has the structure
  • J is a moiety having the structure
  • R 10 is independently at each position methyl or lower alkyl, preferably methyl; R is a moiety selected from the list consisting of
  • a particularly preferred embodiment of the invention is compound 1 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 2 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 3 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 4 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 5 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 6 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 7 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 8 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 9 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 10 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 11 as defined in the Examples section below.
  • Another particularly prefe ⁇ ed embodiment of the invention is compound 12 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 13 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 14 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 15 as defined in the Examples section below.
  • Another particularly preferred embodiment of the invention is compound 16 as defined in the Examples section below.
  • A is a structure wherein
  • J is a moiety having the structure
  • R is methyl or lower alkyl, preferably methyl; R is a moiety having the structure
  • R 6 is a moiety selected from the list consisting of methyl, alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, acyl, aminoacyl, acyloxy, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and hydrogen,
  • R 7 is a moiety selected from the list consisting of alkyl, substituted alkyl, optionally substituted alky), optionally substituted -CH 2 - and -CH(CH 3 ) 2 ; wherein
  • R 6 and R 7 may optionally be joined to form a ring
  • [M] is a covalent bond to the linker
  • R 11 is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence 0, 1 , or 2, but preferably 0, and * is the site of covalent bond with D, respectively, provided that the number of linkers L covalently bound to A is one.
  • the conjugate compound is a structure, wherein R is a moiety having the structure
  • [M] is a moiety having the structure , wherein
  • ** is the site of a covalent bond with A, and R1 and R2 are as defined above.
  • Another preferred embodiment of the invention is a conjugate as described above, wherein A is a structure
  • T is a carbonyl oxygen
  • J is a moiety having the structure
  • R is Cl or halogen
  • R is a moiety having the structure
  • R 8 is a moiety selected from the list consisting of substituted alkyl, aryl, substituted aryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; wherein
  • [M] is a covalent bond to the linker, and R 11 is independently at each position methyl, lower alkyl or halogen, preferably methyl, r is independently at each occurrence 0, 1 , or 2, preferably 0, and * is the site of a covalent bond with D.
  • R and L form a structure selected from the list consisting of
  • * is the site of a covalent bond with D
  • * * * is the site of a covalent bond with B.
  • A is a structure wherein
  • D is a carbon, preferably a carbon in R configuration; T is methyl or lower alkyl; J is a moiety having the structure
  • R 14 is CF 3 , or halogenated alkyl
  • R is a moiety having the structure
  • R 8 is a moiety selected from the list consisting of -CH 2 -, alkyl, substituted alkyl, aryl, substituted aryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic,
  • R 9 is fluorine or halogen
  • [M] is a covalent bond to the linker
  • R 11 is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence 0, 1 , or 2, preferably 0, and * is the site of a covalent bond with D.
  • R and L form a structure
  • R 1 and R 2 have the same meaning as above, * is the site of a covalent bond with D, ** * is the site of a covalent bond with B.
  • A is a structure
  • D is a carbon, preferably a carbon in R configuration
  • T is hydrogen
  • J is a moiety having the structure
  • R 16 , R 17 are independently of each other Cl or halogen; R is a moiety selected from the list consisting of
  • [M] is a covalent bond to the linker; wherein R 11 is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence 0, 1, or 2, preferably 0, * is the site of a covalent bond with D, respectively.
  • J is
  • A is a structure
  • T is a carbonyl oxygen
  • J is a moiety having the structure
  • R is a moiety having the structure
  • R 8 is a moiety selected from the list consisting of substituted alfcyl, aryl, substituted aryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; wherein
  • R 1 ' is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence 0, 1, or 2, preferably O.and * is the site of a covalent bond with D.
  • R and L form a structure
  • R 1 and R 2 have the same meaning as above, * is the site of a covalent bond with D, and
  • A is a structure
  • D is sulphur
  • R is a moiety having the structure
  • R 8 is a moiety selected from the list consisting of substituted alkyl, aryl, substituted aryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; wherein
  • R 11 is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence 0, 1 , or 2, preferably O 1 and
  • R and L form a structure , wherein
  • R 1 and R 2 have the same meaning as above, * is the site of a covalent bond with D, and * ** is the site of a covalent bond with B.
  • A is a structure
  • T is a carbonyl oxygen
  • J is a moiety having the structure
  • R is a moiety having the structure
  • [M] is a covalent bond to the linker; wherein R 11 is independently at each position methyl, lower alkyl or.halogen, r is independently at each occurrence 0, 1 , or 2, preferably 0, and * is the site of a covalent bond with D, respectively.
  • A is a structure
  • R 18 is F or halogen
  • R 19 is CF 3 or halogenated alky
  • R is a moiety having the structure
  • [M] is a covalent bond to the linker; wherein R 11 is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence 0, 1 , or 2, preferably 0, and * is the site of a covalent bond with D, respectively.
  • A is a structure
  • T is a carbonyl oxygen
  • J is a moiety having the structure
  • R is moiety having the structure
  • [M] is a covalent bond to the linker
  • R 11 is independently at each position methyl, lower alkyl or halogen, r is independently at each occurrence O, 1 , or 2, preferably O, and
  • A is a structure
  • T is a carbonyl oxygen
  • J is a moiety having the structure
  • R is moiety having the structure
  • [M] is a covalent bond to the linker
  • Another aspect of the invention relates to a compound of the formula II:
  • A is a BK1 ligand
  • L is a linker covalently bound to A, said linker having the structure
  • X is independently at each occurrence
  • n is independently at each occurrence a positive integer below 20
  • R 3 and R 4 are independently of each other hydrogen, alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, acyl, aminoacyl, acyloxy, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, cycloalkenyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic,
  • R 5 is a moiety selected from the list consisting of alkyl, substituted alkyl, optionally substituted alkyl, optionally substituted alkyl, optionally substituted -CH 2 -, alkylene, alkoxy, substituted alkoxy, alkenyl, substituted alke ⁇ yf, alkynyl, substituted alky ⁇ yl, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, cycloalkenyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, heterocyclic, substituted heterocyclic, thiol, thioalkyj, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, substituted thioheteroaryl, thioheterocyclic, hetero
  • L is selected from the group consisting of
  • a preferred peptide for conjugation via a linker with a biocompatible polymer, according to the invention, is peptide R-892:
  • peptide-linker conjugates are conjugated with biocompatible polymers by standard methods and the methods described herein.
  • Numerous other BK1 antagonist small molecules and peptides are known to the person skilled in the art. Any one of these other BK1 antagonists can be coupled via a linker to a polymer in accordance with the present invention.
  • the invention also relates to the use of conjugates of the invention for the treatment of pain, inflammation and immunological diseases.
  • the invention also relates to the use of conjugates useful as BK1 ligands, preferably but not limited to antagonists or partial agonists, which may relieve adverse symptoms in mammals mediated at least in part by a BK1 receptor including (but not limited to) pain, inflammation and immunological diseases. All individual conjugates can be used, alone or in combination with other conjugates of the invention, for the treatment of the above mentioned indications.
  • Conjugates of the invention can also be used for the preparation of a medicament for the treatment of an inflammatory disease or pain.
  • the use of the conjugates of the invention for the preparation of a medicament for the treatment of an inflammatory disease or pain is a preferred aspect of the current invention.
  • compositions and formulations of conjugates of the invention are pharmaceutical preparations and formulations of conjugates of the invention, as well as their use for the treatment of an inflammatory disease or pain.
  • Such pharmaceutical preparations preferably comprise a conjugate of the invention and a pharmaceutically active carrier.
  • Preferred pharmaceutical preparations are liquid preparations.
  • Other preferred pharmaceutical preparations are liquid preparations for subcutaneous or intramuscular injection.
  • impermissible substitution patterns e.g., methyl substituted with 5 fluoro groups or a hydroxyl group alpha to ethenylic or acetylenic unsaturation. Such impermissible substitution patterns are well known to the skilled artisan.
  • compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).
  • Administration of conjugates of the invention can be, for example, by oral administration, transdermal administration, buccal administration, transmucosal administration, vaginal administration, rectal administration, parenteral administration, and pulmonary administration.
  • the preferred mode of administration is by injection, preferably subcutaneaous injection, or intramuscular injection.
  • compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.” Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like.
  • the compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the therapeutic dosage of the conjugates of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the conjugate, the health and condition of the patient, and the judgment of the prescribing physician.
  • the dose will typically be in the range of about 20 ⁇ g to about 2000 ⁇ g per kilogram body weight, preferably about
  • Suitable dosage ranges for intranasal administration are generally about 0.1 ⁇ g to 1 mg per kilogram body weight. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically-made adjuvant at suitable dosage level in a known way.
  • the preferred preparations are adapted for oral application.
  • These administration forms include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and deposits.
  • the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutan, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, percutan, rectal, subcutaneous, sublingual, topical, or transdermal application, wherein said preparations in addition to typical vehicles and/or diluents contain at least one conjugate according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient.
  • compositions according to the present invention containing at least one conjugate according to the present invention and/or a pharmaceutical acceptable salt thereof as active ingredient will typically be administered together with suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • suitable carrier materials selected with respect to the intended form of administration, i.e. for oral administration in the form of tablets, capsules (either solid filled, semi-solid filled or liquid filled), powders for constitution, gels, elixirs, dispersable granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices.
  • the active drug component may be combined with any oral non-toxic pharmaceutically acceptable carrier, preferably with an inert carrier like lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules) and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the tablet or capsule.
  • Powders and tablets may contain about 5 to about 95 % by weight of a conjugate according to the invention as recited herein or analogues thereof or the respective pharmaceutical active salt as active ingredient.
  • Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.
  • suitable lubricants there may be mentioned boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Suitable disintegrants include starch, methylcellulose, guar gum, and the like.
  • Sweetening and flavoring agents as well as preservatives may also be included, where appropriate.
  • the disintegrants, diluents, lubricants, binders etc. are discussed in more detail below.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effect(s), e. g. antihistaminic activity and the like.
  • Suitable dosage forms for sustained release include tablets having layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example, there may be mentioned water or water/propylene glycol solutions for parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be present in combination with a pharmaceutically acceptable earner such as an inert, compressed gas, e. g. nitrogen.
  • a pharmaceutically acceptable earner such as an inert, compressed gas, e. g. nitrogen.
  • a low melting wax such as a mixture of fatty acid glycerides like cocoa butter is melted first, and the active ingredient is then dispersed homogeneously therein e. g. by stirring. The molten, homogeneous mixture is then poured into conveniently sized moulds, allowed to cool, and thereby solidified.
  • transdermal compositions may have the form of a cream, a lotion, an aerosol and/or an emulsion and may be included in a transdermal patch of the matrix or reservoir type as is known in the art for this purpose.
  • capsule refers to a specific container or enclosure made e. g. of methylcellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredient(s).
  • Capsules with hard shells are typically made of blended or relatively high gel strength gelatins from bones or pork skin.
  • the capsule itself may contain small amounts of dyes, opaquing agents, plasticisers and/or preservatives.
  • Under tablet a compressed or moulded solid dosage form is understood which comprises the active ingredients with suitable diluents.
  • the tablet may be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, or by compaction well known to a person of ordinary skill in the art.
  • Oral gels refer to the active ingredients dispersed or solubilised in a hydrophilic semisolid matrix.
  • Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended e. g. in water or in juice.
  • suitable diluents are substances that usually make up the major portion of the composition or dosage form.
  • Suitable diluents include sugars such as lactose, sucrose, mannitol, and sorbitol, starches derived from wheat, corn rice, and potato, and celluloses such as microcrystalline cellulose.
  • the amount of diluent in the composition can range from about 5 to about 95 % by weight of the total composition, preferably from about 25 to about 75 % by weight, and more preferably from about 30 to about 60 % by weight.
  • disintegrants refers to materials added to the composition to support disintegration and release of the pharmaceutically active ingredients of a medicament.
  • Suitable disintegrants include starches, "cold water soluble" modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar, cellulose derivatives such as methylceliulose and sodium carboxymethylcellulose, microcrystalline celluloses, and cross-linked microcrystalline celluloses such as sodiumcroscaramellose, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures.
  • the amount of disintegrant in the composition may range from about 2 to about 20 % by weight of the composition, more preferably from about 5 to about 10 % by weight.
  • Binders are substances which bind or "glue” together powder particles and make them cohesive by forming granules, thus serving as the "adhesive" in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose, starches derived from wheat corn rice and potato, natural gums such as acacia, gelatin and tragacanth, derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate, cellulose materials such as methylceliulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminum silicate. The amount of binder in the composition may range from about 2 to about 20 % by weight of the composition, preferably from about 3 to about 10 % by weight, and more preferably from about 3 to about 6 % by weight.
  • Lubricants refer to a class of substances which are added to the dosage form to enable the tablet granules etc. after being compressed to release from the mould or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and D,L-leucine. Lubricants are usually added at the very last step before compression, since they must be present at the surface of the granules.
  • the amount of lubricant in the composition may range from about 0.2 to about 5 % by weight of the composition, preferably from about 0.5 to about 2 % by weight, and more preferably from about 0.3 to about 1.5 % by weight of the composition.
  • Glidents are materials that prevent baking of the components of the pharmaceutical composition together and improve the flow characteristics of granulate so that flow is smooth and uniform.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition may range from about 0.1 to about 5 % by weight of the final composition, preferably from about 0.5 to about 2 % by weight.
  • Coloring agents are excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent may vary from about 0.1 to about 5 % by weight of the composition, preferably from about 0.1 to about 1 % by weight.
  • the invention also provides a method for administering a conjugate as provided herein to a patient suffering from a condition that is responsive to treatment with the conjugate.
  • the method comprises administering, generally orally, a therapeutically effective amount of the conjugate (preferably provided as part of a pharmaceutical preparation).
  • Other modes of administration are also contemplated, such as pulmonary, nasal, buccal, rectal, sublingual, transdermal, and parenteral.
  • the conjugate or pharmaceutical composition comprising the conjugate is administered directly to the eye, preferably in form of eye drops.
  • a therapeutically effective amount will range from about 0.001 mg to 100 mg/day, preferably in doses from O.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/day to 50 mg/day.
  • any given conjugate (preferably provided as part of a pharmaceutical preparation) can be administered in a variety of dosing schedules depending on the judgment of the clinician, needs of the patient, and so forth.
  • the specific dosing schedule will be known by those of ordinary skill in the art or can be determined experimentally using routine methods.
  • Exemplary dosing schedules include, without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, three times weekly, twice weekly, , once weekly, twice monthly, once monthly, and any combination thereof.
  • One advantage of administering the conjugates of the present invention is that a reduction in first pass metabolism may be achieved relative to the parent drug. Such a result is advantageous for many orally administered drugs that are substantially metabolized by passage through the gut. In this way, clearance of the conjugate can be modulated by selecting the polymer molecular size, linkage, and position of covalent attachment providing the desired clearance properties.
  • Preferred reductions in first pass metabolism for a conjugate as compared to the corresponding non-conjugated small drug molecule include: at least about 5%, at least about 10%, at least about 20%, at least about 40; at least about 60%, at least about 80% and at least about 90%.
  • the present invention also includes pharmaceutical preparations comprising a conjugate as provided herein in combination with a pharmaceutical excipient.
  • the conjugate itself will be in a solid form (e.g., a precipitate), which can be combined with a suitable pharmaceutical excipient that can be in either solid or liquid form.
  • Exemplary excipients include, without limitation, those selected from the group consisting of carbohydrates, inorganic salts, antimicrobial agents, antioxidants, surfactants, buffers, acids, bases, and combinations thereof.
  • a carbohydrate such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer may be present as an excipient.
  • Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, verbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the
  • the excipient can also include an inorganic salt or buffer such as citric acid sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.
  • an inorganic salt or buffer such as citric acid sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.
  • the preparation may also include an antimicrobial agent for preventing or deterring microbial growth.
  • antimicrobial agents suitable for the present invention include benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, thimersol, and combinations thereof.
  • An antioxidant can be present in the preparation as well. Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the conjugate or other components of the preparation. Suitable antioxidants for use in the present invention include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.
  • a surfactant may be present as an excipient.
  • exemplary surfactants include: polysorbates, such as "Tween 20" and 'Tween 50" and pluronics such as F68 and F88 (both of which are available from BASF, Mount Olive, New Jersey); sorbitan esters, lipids, such as phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines (although preferably not in liposomal form), fatty acids and fatty esters; steroids, such as cholesterol; and chelating agents, such as EDTA, zinc and other such suitable cations. Acids or bases may be present as an excipient in the preparation.
  • Non-limiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.
  • suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium, hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.
  • the amount of the conjugate in the composition will vary depending on a number of factors, but will optimally be a therapeutically effective dose when the composition is stored in a unit dose container.
  • a therapeutically effective dose can be determined experimentally by repeated administration of increasing amounts of the conjugate in order to determine which amount produces a clinically desired endpoint.
  • the excipient will be present in the composition in an amount of about 1 % to about 99% by weight, preferably from about 5%-98% by weight, more preferably from about 15-95% by weight of the excipient, with concentrations less than 30% by weight most preferred.
  • compositions can take any number of forms and the invention is not limited in this regard.
  • Exemplary preparations are most preferably in a form suitable for oral administration such as a tablet, caplet, capsule, gel cap, troche, dispersion, suspension, solution, elixir, syrup, lozenge, transdermal patch, spray, suppository, and powder.
  • Oral dosage forms are preferred for those conjugates that are orally active, and include tablets, caplets, capsules, gel caps, suspensions, solutions, elixirs, and syrups, and can also comprise a plurality of granules, beads, powders or pellets that are optionally encapsulated.
  • Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts.
  • Tablets and caplets for example, can be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred when preparing tablets or caplets containing the conjugates described herein.
  • the tablets and caplets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like. Binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact.
  • Suitable binder materials include, but are not limited to, starch (including corn starch and pre-gelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum.
  • Lubricants are used to facilitate tablet manufacture, promoting powder flow and preventing particle capping (i.e., particle breakage) when pressure is relieved.
  • Useful lubricants are magnesium stearate, calcium stearate, and stearic acid.
  • Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums, or cross-linked polymers.
  • Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol.
  • Stabilizers as well known in the art, are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.
  • Capsules are also preferred oral dosage forms, in which case the conjugate- containing composition can be encapsulated in the form of a liquid or gel (e.g., in the case of a gel cap) or solid (including particulates such as granules, beads, powders or pellets).
  • Suitable capsules include hard and soft capsules, and are generally made of gelatin, starch, or a cellulosic material. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like.
  • parenteral formulations in the substantially dry form typically as a lyophilizate or precipitate, which can be in the form of a powder or cake
  • formulations prepared for injection which are typically liquid and requires the step of reconstituting the dry form of parenteral formulation.
  • suitable diluents for reconstituting solid compositions prior to injection include bacteriostatic water for injection, dextrose 5% in water, phosphate- buffered saline, Ringer's solution, saline, sterile water, de- ionized water, and combinations thereof.
  • compositions intended for parenteral administration can take the form of non-aqueous solutions, suspensions, or emulsions, each typically being sterile.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • the parenteral formulations described herein can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • the formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat.
  • the conjugate can also be administered through the skin using conventional transdermal patch or other transdermal delivery system, wherein the conjugate is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin.
  • the conjugate is contained in a layer, or "reservoir,” underlying an upper backing layer.
  • the laminated structure can contain a single reservoir, or it can contain multiple reservoirs.
  • Preferred formulations of the invention are ophthalmic formulations, preferably in a form which can be directly applied to the eye, more preferably in form of eye drops.
  • inflammatory diseases as used herein relates to diseases triggered by cellular or non-cellular mediators of the immune system or tissues causing the inflammation of body tissues and subsequently producing an acute or chronic inflammatory condition.
  • hypersensitivity reactions of type I-IV for example but not limited to hypersensitivity diseases of the lung including asthma, atopic diseases, allergic rhinitis or conjunctivitis, angioedema of the lids, hereditary angioedema, antireceptor hypersensitivity reactions and autoimmune diseases, Hashimoto's thyroiditis, systemic lupus erythematosus, Goodpasture's syndrome, pemphigus, myasthenia gravis, Grave's and Raynaud's disease, type B insulin-resistant diabetes, rheumatoid arthritis, psoriasis, Crohn's disease, scleroderma, mixed connective tissue disease, polymyositis, sarcoidosis, Wegener's granulomatosis, glomerulonephritis, acute or chronic host versus graft reactions.
  • hypersensitivity diseases of the lung including asthma, atopic diseases, allergic rhinitis or conjunctivitis, angioedema
  • inflammatory diseases includes but is not limited to abdominal cavity inflammation, dermatitis, gastrointestinal inflammation (including inflammatory bowel disease, ulcerative colitis), fibrosis, ocular and orbital inflammation, mastitis, otitis, mouth inflammation, musculoskeletal system inflammation (including gout, osteoarthritis), inflammatory diseases of the central nervous system (including multiple sclerosis, bacterial meningitis, meningitis), genitourinary tract inflammation (incl prostatitis, glomerulonephritis), cardiovascular inflammation (including atherosclerosis, heart failure), respiratory tract inflammation (including chronic bronchitis, chronic obstructive pulmonary disease), thyroiditis, diabetes mellitus, osteitis, myositis, multiple organ failure (including, sepsis), polymyositis and psoriatic arthritis.
  • Inflammatory diseases which can be treated with compounds of the invention are asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), rheumatoid arthritis, rhinitis, pancreatitis, cystitis, uveitis, inflammatory skin disorders, rheumatic disease, tenosynovitis, gout, liver disease, atherosclerosis, septic shock, headache, migraine, irritable bowel syndrome, tissue transplantation rejection, tumor metastasis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and ulcerative colitis.
  • Crohn's disease is an idiopathic, chronic ulceroconstrictive inflammatory disease characterized by sharply delimited and typically transmural involvement of all layers of the bowel wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and/or colon.
  • Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury.
  • Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways.
  • the stimuli cause release of various mediators of inflammation from IgE-coated mast cells including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet activating factor. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory injury.
  • Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aorta and iliac).
  • the basic lesion, the atheroma consists of a raised focal plaque within the intima, having a core of lipid and a covering fibrous cap.
  • Atheromas compromise arterial blood flow and weaken affected arteries.
  • Myocardial and cerebral infarcts are a major consequence of this disease.
  • Macrophages and leukocytes are recruited to atheromas and contribute to inflammatory injury.
  • Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints.
  • Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees.
  • the arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See e.g., Paul, Immunology (3d ed., Raven Press, 1993).
  • the formulations of the present invention are especially useful in the treatment of multiple sclerosis, rheumatoid arthritis and asthma.
  • a further use of the conjugates of this invention is in treating multiple sclerosis.
  • Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated
  • Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating sheath covering nerve fibers.
  • Pain Conjugates of the invention are also useful in the treatment of pain.
  • pain generally relates to any type of pain and broadly encompasses types of pain such as acute pain, chronic pain, inflammatory and neuropathic pain.
  • pain comprises neuropathic pain and associated conditions.
  • the pain may be chronic, allodynia (the perception of pain from a normally innocuous stimulus), hyperalgesia (an exaggerated response to any given pain stimulus) and an expansion of the receptive field (i.e. the area that is "painful" when a stimulus is applied), phantom pain or inflammatory pain.
  • Acute pain types comprise, but are not limited to pain associated with tissue damage, postoperative pain, pain after trauma, pain associated with dental extraction, pain caused by burns, pain caused by local or systemic infection, visceral pain associated with diseases comprising: pancreatits, intestinal cystitis, dysmenorrhea, Irritable Bowel syndrome, Crohn's disease, ureteral colic and myocardial infarction
  • pain comprises pain associated with CNS disorders comprising: multiple sclerosis, spinal cord injury, traumatic brain injury, parkinson's disease and stroke
  • pain relates to chronic pain types comprising headache
  • migraine disorders for example migraine disorders, episodic and chronic tension-type headache, tension-type like headache, cluster headache, and chronic paroxysmal hemicrania
  • low back pain cancer pain, osteoarthritis pain, pain associated with angina and menstruation, and neuropathic pain, but is not limited thereto.
  • Inflammatory pain (pain in response to tissue injury and the resulting inflammatory process) as defined herein relates to imflammatory pain associated with diseases comprising connective tissue diseases, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and arthritis, but is not limited thereto.
  • Neuropathic pain (pain resulting from damage to the peripheral nerves or to the central nervous system itself) includes conditions comprising, but not limited to metabolic neuropathies (e.g., diabetic neuropathy), post-herpetic neuralgia, trigeminal neuralgia, cranial neuralgia, post-stroke neuropathic pain, multiple sclerosis-associated neuropathic pain, HIV/AIDS-associated neuropathic pain, cancer-associated neuropathic pain, carpal tunnel- associated neuropathic pain, spinal cord injury-associated neuropathic pain, complex regional pain syndrome, fibromyalgia-associated neuropathic pain, reflex sympathic dystrophy, phantom limb syndrome or peripheral nerve or spinal cord trauma, nerve transection including surgery, limb amputation and stump pain, pain caused by the side effects of anti-cancer and anti-AIDS therapies, post-surgical neuropathic pain, neuropathy-associated pain such as in idiopathic or post-traumatic neuropathy and mononeuritis, and neuropathic pain
  • allodynia denotes pain arising from stimuli which are not normally painful. Allodynic pain may occur other than in the area stimulated.
  • hyperalgesia denotes an increased sensitivity to a painful stimulus.
  • hypoalgesia denotes a decreases sensitivity to a painful stimulus.
  • the conjugates of the present invention are also useful in the treatment and/or prevention of immunological diseases, preferably, autoimmune diseases. Accordingly, the present invention provides a method for the treatment and/or prevention of immunological diseases comprising the administration of an effective amount of conjugates of the invention to a subject in need thereof.
  • immunological diseases include diabetes, rheumatic diseases, AIDS, chronic granulomatosis disease, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary diseases, osteoporosis, ulcerative colitis, Crohn's disease, sinusitis, lupus erythematosus, psoriasis, multiple sclerosis, myasthenia gravis, alopecia, recurrent infections, atopic dermatitis, eczema and severe anaphylactic reactions, but are not limited thereto.
  • immunological diseases also include allergies such as contact allergies, food allergies or drug allergies. Use in Qphtalmolo ⁇ v
  • the conjugates of the present invention are particularly useful in the treatment and/or prevention of ophthalmic diseases.
  • Using conjugates or pharmaceutical preparations of the invention in a form which can be directly applied to the patient's eye, such as in form of an eye drop, will keep the BK1 antagonist contained to the eye space and will avoid systemic circulation.
  • the present invention also relates to pharmaceutical preparations comprising conjugates of the invention, wherein said pharmaceutical preparation is for ophthalmic use.
  • the pharmaceutical preparation is applied directly to the patient's eye, preferably in form of an eye drop.
  • the invention also relates to the use of such pharmaceutical preparation in the treatment of ophthalmic diseases, as well as to methods of preparation of such pharmaceutical compositions.
  • Example 5 Preparation of r5-(4-Cvano-benzylamino)-pentv ⁇ -carbamic acid tert-butyl ester.
  • Example 6 Preparation of (3-f2-f2-f3-ff4-Cvano-benzyl)-(2-f2-f(4-methoxy-2.6- dimethyl-benzenesulfonvD-metriyl-aminoi-ethoxyl-acetylVaminol-propoxyVetrioxyV-etrioxyl- propyDcarbamic acid tert-butyl ester
  • Example 7 Preparation of l5-f(4-Cvano-benzyl)-(242-r(4-methoxy-2,6-dimethyl- benzenesulfonylVmethyl-aminol-ethoxyVacetylVaminoi-pentvOcarbamic acid tert-butvl ester
  • Example 8 Preparation of ⁇ 5-r(4-(4.5-dihvdro-1H-imidazol-2-v0-benzylV(242-r(4- methoxy-2.6-dimethyl-benzenesulfonylVmethyl-amino1-etho ⁇ y)-acetylVaminol- pentvDcarbamic acid tert-butyl ester (Compound 1 )
  • Example 10 Preparation of N-(3 ⁇ f2-f2-(3-Amino-propoxy)-ethoxy1-ethoxy>-propyO-N- [4-(4.5-dihvdro-1 H-imidazol-2-ylV-benzvn-2-(2-r(4-methoxy-2.6-dimethyl-benzenesulfonylV methyl-aminoi-ethoxyVacetamide
  • Example 11 Preparation of N-(5-Amino-pentyl)-N-r4-(4.5-dihvdro-1 H-imidazol-2-v ⁇ - benzyll-2-(2-f(4-methoxy-2.6-dimethyl-benzenesulfonyl)-methyl-aminol-ethoxy ⁇ -acetamide.
  • Example 12 Preparation of (6- ⁇ 3-[2-(2- ⁇ 3-[[4-(4.5-Dihydro-1H-imidazol-2-yl)-benzyll- (2-(2-[(4-methoxy-2.6-dimethyl-benzenesulfonyl)-methyl-aminol-ethoxy ⁇ -acetyl)-amino]- propoxy ⁇ ethoxy ⁇ ethoxyl-propylcarbamyloyl ⁇ -hexyll-carbamic acid tert-butyl ester (Compound 4 ⁇
  • the aqueous phase was extracted with ethyl acetate and the combined organic portions were washed with brine and dried over sodium sulfate and the solvent was removed under reduced pressure.
  • the crude material was purified by chromatography on silica (40 g, 0-8% MeOH in CH 2 CI 2 (1 % NH 4 OH)). The product was obtained as a clear oil (0.35 g, 61 %).
  • Compounds 1-16, inclusive are all BK1 antagonists.
  • Example 18 Design and Placement of Linkers for BK1 antagonist conjugates
  • Placement of linker attachment on the BK1 antagonist was determined utilizing the homology model published by Ha and coworkers ⁇ Biochem. Biophysical Res. Comm. 2005, 331 , 159-166). These workers have utilized this model to dock 2-[1-(3,4-Dichloro- benzenesulfonyl)-3-oxo-1 ,2,3,4-tetrahydro-quinoxalin-2-yl]-N- ⁇ 2-[4-(4,5-dihydro-1 H-imidazol- 2-yl)-phenyl]-ethyl ⁇ -acetamide and related analogs. Site-directed mutagenesis data was utilized to help select the best pose. Ha and coworkers have found very good agreement between the calculated antagonist-receptor binding energy and the experimentally measured binding affinities (Ki) of several related analogs.
  • This model was utilized for finding potential sites for covalent placement of a large linker that maintained the small molecule antagonist in the active site. The goal was to find sites of attachment that were chemically feasible and allowed the biocompatible polymer to be located in solvent space outside BK1. Published SAR was also utilized to assist in this effort. Low energy conformations of each of the small molecule BK1 antagonists were docked into the Ha homology model and potential sites for linker attachment were evaluated. Known SAR was also utilized to help in this effort.
  • the signs of pain are measured by quantifiable behavioral components such as, e.g., paw withdrawal threshold to thermal stimulation using a laser source or to mechanical stimulation with von Frey hairs.
  • quantifiable behavioral components such as, e.g., paw withdrawal threshold to thermal stimulation using a laser source or to mechanical stimulation with von Frey hairs.
  • the carrageenan assay in mice is a well known behavioral model of nociception in inflammatory pain. It is sensitive to various classes of analgesic drugs.
  • the noxious stimulus consists of an injection of 25 ⁇ l of 1 ,5% carrageenan (in saline) into a single hind paw (ipsi- lateral paw) of mice. Subsequent inflammation results in long lasting swelling and hypersensitivity (against mechanical and thermal stimuli) of the paw.
  • the carrageenan assay is a standard laboratory assay used to predict anti-inflammatory activity of test compounds. Hargreaves Assay (withdrawal of paws due to thermal stimulation via a light source) and paw oedema measurements are used for read out.
  • the basic measurement consists of measuring thermal as well as mechanical hypersensitivity and paw oedema in response to irritants, such as carrageenan. Inflammation and resulting inflammatory pain is induced by subcutaneous injection of
  • mice 25 ⁇ l of 1 ,5% carrageenan (in saline) into mice hind paw (ipsi-lateral paw).
  • Each group of 10 mice receives administration of compound A , 40 mg/kg body weight or equimolar amounts of compounds B or C, vehicle (200 ⁇ l of PBS or DTPB-20-5,5 (5% DMSO, Tris, phosphate buffer) or Naproxen (50 mg/kg bodyweight) as a positive control by i.p. injection 3 hours after carrageenan application. Contra-lateral paws do not receive carrageenan injection.
  • Figure 2 depicts the effect of administration of compound C, i.e. a conjugate of compound A coupled via a linker to a 2 kDa polyethylene glycol (PEG) polymer to carrageenan-treated mice.
  • compound C i.e. a conjugate of compound A coupled via a linker to a 2 kDa polyethylene glycol (PEG) polymer to carrageenan-treated mice.
  • PEG polyethylene glycol
  • Compound B (Compound 4)
  • a Hargreaves Assay As a read-out of the carrageenan assay, a Hargreaves Assay was performed, wherein said assay allows the measuring of thermal sensitivity to radiant heat.
  • the Hargreaves assay (Hargreaves et al., 1988) measures nociceptive sensitivity in a freely moving animal by focusing a radiant heat source on the plantar surface of an animal's hind paw as it stands in a plexiglass chamber. Specifically, the lower side of a paw is exposed to a luminous source, generating a temperature of, e.g., 55°C. Thermal sensitivity is measured as latency between start of exposure and lifting/pulling the exposed paw.
  • Paw withdrawal latency (PWL) of the ipsi-lateral hind paw serves as surrogate marker for nociceptive sensitivity and is measured at several time points 3 hours after carrageenan injection: Contra-lateral paw: immediately before compound injection, ipsi-lateral paw: immediately before, 15 min, 30 min and 60 min after compound application.
  • carrageenan treatment resulted in pronounced hyperalgesia of the ipsi-lateral paw compared to the contra-lateral side of all mice as indicated by the decreased paw withdrawal latency of about 5 sec 3 hrs after carrageenan injection.
  • mice which received compound A treatment displayed a reversal of hyperalgesia with a maximum at 15 min after compound application.
  • Compound B treatment also resulted in a reversal of the hyperalgesia effect. In comparison to compound A the effect of compound B was more pronounced and prolonged at least up to 60 min after injection.
  • mice being treated with compound C displayed a similar increase of paw withdrawal latencies in the Hargreaves assay compared to compound A receiving animals. Both groups reached a maximum of PWL at the time point of 15 min, which continuously decreased until at least 60min after compound application.
  • BK1 antagonistic properties of test compounds are determined in a functionsl Ca 2+ (human) Bradykinin B1 Receptor assay.
  • the following protocol provides a general process for the assay. Incubation times, drug addition times and amounts may be changed according to cell density, activity and assay variables.
  • the assay is commercially available from NovaScreen (Hanover, Maryland, USA, www.novascreen.com, Cat #: 300-0283).
  • Reference compound [des-Arg10]-HOEUO (CAS No. 138680-92-9) is available from Sigma (Cat. No. H158) or AnaSpec (San Jose, CA, USA, Cat. No. 22970).
  • Human rhabdomyosarcoma (muscle-derived) cells are seeded at about 1e4 cells/well in 100 ⁇ L per well in a 96 well clear bottom plate. Cells are incubated overnight at 37°C.
  • Fluorometer (Flexstation) temperature is set to 37 0 C. Cell plate, compound plate and injection tips are placed in Flexstation for 15 min to equilibrate to assay temperature.

Abstract

L'invention concerne des antagonistes de BK1 conjugués. Les antagonistes de BK1 conjugués comprennent une petite molécule ou un peptide, lié de façon covalente à une molécule lieur, elle-même liée de façon covalente à un polymère biocompatible tel que le PEG. La molécule lieur et les antagonistes de BK1 conjugués biocompatibles de l'invention sont utiles dans le traitement de diverses maladies, y compris des maladies auto-immunes et la douleur.
PCT/US2008/007157 2007-06-08 2008-06-06 Conjugués antagonistes de bk1 WO2008153967A1 (fr)

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