EP2139461A2 - Amino derivatives to prevent nephrotoxicity and cancer - Google Patents

Amino derivatives to prevent nephrotoxicity and cancer

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Publication number
EP2139461A2
EP2139461A2 EP08715624A EP08715624A EP2139461A2 EP 2139461 A2 EP2139461 A2 EP 2139461A2 EP 08715624 A EP08715624 A EP 08715624A EP 08715624 A EP08715624 A EP 08715624A EP 2139461 A2 EP2139461 A2 EP 2139461A2
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EP
European Patent Office
Prior art keywords
alkyl
use according
group
heterocyclyl
alkynyl
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EP08715624A
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German (de)
French (fr)
Inventor
Søren Valdgård BOYE
Jacob Thinggaard
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • A—HUMAN NECESSITIES
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    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
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    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the technical field of cell toxicity treatment and discloses compounds and combination medicaments for use in such treatment.
  • the invention relates to compounds for the prevention of organ damage, in particular organ damage of the kidneys and the inner ear induced by the administration of therapeutic agents.
  • Prominent drugs in clinical use are toxic to tissues like the kidney and inner ear.
  • Prominent drugs in this category are cisplatin, ifosfomide, cyclosporine, amphotericin B, valproate, polymyxin B and therapeutic antibodies.
  • aminoglycosides which are among the most important antibiotics for the treatment of severe bacterial infections. They are the preferred agents against a number of Gram-negative bacteria. Above all, this is due to a general increase in the occurrence of pathological strains resistant to other classes of antibiotics. This may positively influence the market share of aminoglycosides.
  • the main obstacle in the clinical use of the above drugs is their severe oto- and nephrotoxic (ear and kidney) side effects, which may lead to complete loss of hearing and to renal failure.
  • the use of these drugs is thus not only associated with a high risk but also entails high costs for drug monitoring and diagnosis. Their use is therefore restricted to incidences of the most severe infections in the industrial countries.
  • aminoglycosides are used more frequently because of their low production costs, aminoglycosides account for 70% of all cases of acquired deafness.
  • the underlying mechanisms causing toxicity are not understood. So far it is known that the drugs bind to the surface of cells in the kidneys and the inner ear and are taken up into the cells through unknown mechanisms. As the drugs are poorly degradable in the cells, they accumulate intracellular ⁇ leading to the destruction of cell structures and thus to renal damage and hearing loss.
  • Various surface structures or receptors have been held responsible for the binding and uptake of the antibiotics.
  • megalin a surface receptor of the kidneys, is responsible for the uptake of antibiotics (Moestrup et al., J. CIIn. Invest. 96, 1404-1413, 1995).
  • Megalin is a 600 kDa endocytosis receptor of the low-density lipoprotein (LDL) receptor gene family.
  • Megalin is a multifunctional clearance receptor that binds and internalises a number of macromolecules. The sequence for megalin is shown as: cDNA: U33837; gene: NT_002176.
  • Cubilin is a 460 kDa membrane-associated protein colocalizing with megalin, which may facilitate the endocytic process by sequestering the antibiotic/therapeutic agent on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand.
  • the therapeutic agent may bind to cubilin as well as directly to megalin.
  • Cubilin appears not to be able to mediate endocytosis on its own but physically associates with megalin and internalizes in a complex with this receptor.
  • the sequence for cubilin is shown as: cDNA: XM 01 1904; gene: NT 008682 (Homo sapiens chromosome 10 working draft sequence segment).
  • the article does not disclose cell toxicity reducing compounds or medicaments capable of binding to a receptor cubilin and/or a receptor megalin and/or a co-receptor of megalin and cubilin.
  • the present invention relate to use of a compound comprising a structure of the general formula (I):
  • m is an integer between 1 -100, for example 1 -50, such as 1 1 -20, for example 1 -10, and L is of the general formula (II):
  • X is a bond or a C1 -12 alkyl or an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyl comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O) 0-2 or carbonyl, and
  • n is an integer between 1 and 12, and
  • any component of X may individually be substituted with Z, j times wherein j is an integer from 1 to 12 and wherein Z is a substituent to X of the general formula
  • each substituent Z may exist in a copies wherein a is an integer from 1 to 12, wherein the optional substituents Ri, R 2 , R 3 and R 4 individually are selected from a bond to X, or a bond to R 1 , or a bond to R 2 , or a bond to R 3 , or a bond to R 4 , or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C 1 - 12 )-alkyl-aryl, (d- 12 )-alkoxyaryl, heteroaryl-(d- 12 )-alkyl, heterocyclyl-(C 1 .
  • R 1 is a hydrogen
  • R 2 is 1 -imino- aminomethyl
  • R 3 selected from any of the above, connecting the thus formed guanidino group to X, wherein any of the substituents R 1 , R 2 , R 3 or R 4 , optionally may be substituted individually at least once, wherein the substituents are selected from: hydrogen, O, OH, phenyl, amine (NH 2 ), imine (NH), aminoalkyl, aminopolyalkyl, alkylamin, hal
  • R 1 , R 2 , R 3 and R 4 can be a bond connecting to X wherein any component of X optionally may be substituted with Y, k times wherein k is an integer between O and 12 and wherein Y is a substituent described by the general formula (IV):
  • each substituent Y may exist in b copies wherein b is an integer from 1 to 12, wherein the optional substituents R 5 , R 6 , R7, Rs and R 9 individually are selected from a bond to X or a bond to R 5 , or a bond to R 6 , or a bond to R 7 , or a bond to R 8 , or a bond to R 9 , or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (d-i 2 )-alkyl-aryl, (d-i 2 )-alkoxyaryl, heteroaryl-(Ci_ i 2 )-alkyl, heterocyclyl-(d-i 2 )-alkyl, alkylated cycloalkyl, cycloalkyl, alkyl
  • any of the carbons comprised by Y is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R 5 , R 6 , R 7 and R 8 can be a bond connecting to X, or wherein one or more of the optional substituents R 5 , R 6 , R 7 and R 8 individually or in conjunction are optionally linked to one or more of the optional substituent(s) Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and/or to N of formula III and/or to X of formula (II) and or to one of said optional substituents of said Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 thereby forming one or more rings,
  • X is a bond linking R 2 to R 5 to R 9 that may be a N linked to R 8 to R 3 thus forming a ring Q, said Q being a piperazine or piperidine ring, thereby forming the general formula V.
  • R 1 , R 4 , R 6 and R 7 are optional substituents as defined, wherein the general formula I comprises one ore more amino groups individually selected from primary or secondary or tertiary amines or where the amino group optionally have a further substituent attached thus forming a quaternary ammonium,
  • X of formula (II) is phenyl then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or ethylamine or 2-amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or
  • R 1 , R 4 , R 6 and R 7 are not selected among N-linked C (2 - 3) -alkylamine and a para-oriented amino group respectively, nor among N-linked hydrogen and para-oriented C (2 - 3) -alkylamine respectively,
  • the invention in one aspect, relates to a method for the treatment and/or prophylactic treatment of induced cell toxicity, in particular nephrotoxicity and/or ototoxicity, comprising the administration of a compound of formula (I), to a person in need thereof.
  • each definition is inde- pendent.
  • the invention relates to a compound having the general formula of wherein
  • A is independently selected from formula (I) and/or formula (II) and/or formula (III) and/or formula (IV) and/or formula (V) and/or formula (Vl) and/or formula (VII) and/or formula (VIII) as defined above (I) as defined herein, and wherein D is a spacer, q is an integer of 1 -100, p is an integer of 1 -100.
  • a combination medicament comprising a compound of the invention or any of the compounds for which a use is described herein and a therapeutic agent for simultaneous, separate or sequential use in cell toxicity therapy, said cell presenting a receptor megalin and/or a receptor cubilin and/or a co-receptor of megalin and cubilin is disclosed.
  • the principle of the present invention is to reduce the side effects caused by therapeutic agents, in particular kidney and inner ear damage.
  • the toxicity of the therapeutic agents is due to the accumulation of the therapeutic agent in cells in the organs in question.
  • the invention focuses on preventing said accumulation in cells. This may for example be performed by inhibiting the binding of the therapeutic agent to the receptor megalin by either blocking a sufficient amount of binding sites on the receptor megalin and/or blocking the therapeutic agent so that it maintains the normal therapeutic effect but is prevented from binding to the receptor.
  • Alkenyl group means a non-saturated linear or branched hydrocarbon group including, for example, methylene or ethylene.
  • Alkyl group means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like.
  • Preferred alkyls are lower alkyls, i.e. alkyls having 1 to 6 carbon atoms, such as 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • Alkynyl group means a non-saturated linear or branched hydrocarbon group including, for example, ethynyl or propynyl.
  • Aryl represents a hydrocarbon comprising at least one aromatic ring, and may contain from 5 to 18, preferably from 6 to 14, more preferably from 6 to 10, and most preferably 6 carbon atoms.
  • Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenylenyl, and fluorenyl groups.
  • Particularly preferred aryl groups include phenyl, naphthyl and fluorenyl, with phenyl being most preferable.
  • Cell death in the present context cell death is defined in various ways and covers a cell which has lost all its functions, a cell which has lost a special function, such as hormone synthesis, or a cell which has a reduced capability for further division.
  • Cell toxicity an agent is defined as toxic when it is directly capable of causing cell death.
  • Cycloalkyl means a monovalent saturated carbocyclic compound consisting of one or two rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, aryl- aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylamino- carbonyl, alkylcarbonylamino and arylcarbonylamino.
  • Form a ring means that the atoms mentioned are connected through a bond when the ring structure is formed.
  • ring is used synonymously with the term “cyclic”.
  • Heteroalkyl is a saturated linear or branched hydrocarbon group (including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like) wherein one or more carbon atoms are substituted for a heteroatom selected from N, O, S, S(O) 0-2 , Si or P and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosul
  • Heteroalkyls of the present invention may be branched or unbranched and may range from one (1 ) to fifty (50) carbon atoms in length wherin 50% or less, of said carbon atoms may be substituted for N, NH(Q -4 ), O, S, S(O) 0-2 , Si, P, Cl, Br.
  • Heterocvclyl means a monovalent saturated cyclic compound or part of a compound, consisting of one to two rings, of three to eight atoms per ring, incorporating one, two, three or four ring heteroatoms, selected from N, O or S(O) 0-2 , and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, arylaminocarbonyl, al
  • heterocyclyls of the present invention include, but is not limited to piperazine and piperidine which may thus be heterocyclyl substituents as defined herin. Such substituents may also be denoted piperazino and piperidino respectively.
  • a further heterocyclyl of the present invention is thiophene.
  • Heteroaryl means a monovalent aromatic cyclic compound or part of a compound having one to three rings, of four to eight atoms per ring, incorporating one, two, three or four heteroatoms (selected from nitrogen, oxygen, or sulfur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonlamino and arylcarbonylamino.
  • Induced cell toxicity means a toxic response induced by a therapeutic agent in a cell being exposed to said therapeutic agent.
  • Monomer A small entity such as a molecule that may become chemically bonded to other monomers to form an oligomer, polymer or multimer.
  • Oligomer A substance consisting of two or more repeating structural units, monomers, connected by chemical bonds.
  • Polymer A substance consisting of a very large number of repeating structural units, monomers, connected by chemical bonds.
  • Polymorph Variation in chemical and physical properties of a compound such as e.g. crystal lattice, melting point, chemical reactivity, apparent solubility, dissolution rate, optical and electrical properties, vapour pressure, and density.
  • Prophylaxis or prophylactic treatment is not intended to be limited to complete prevention of induced cell toxicity, but also includes incomplete reduction of such toxicity.
  • Rational number A number which can be expressed as a ratio of two integers.
  • Spacer in the present context refers to the atoms directly linking the monomers of formula (I), (II), (III), (IV) or (V).
  • the spacer may also directly link the compounds of formula (I), (II), (III), (IV) or (V) to a therapeutic agent as described by the present combination medicament.
  • Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
  • Therapeutic agent is used synonymously with a medicament, unless otherwise stated.
  • the compounds of the invention may bind to a receptor involved in induced cell toxicity, such as megalin and cubilin, preferably megalin, in order to inhibit binding and optionally uptake of the therapeutic agent into the cell.
  • a receptor involved in induced cell toxicity such as megalin and cubilin, preferably megalin
  • the compound is preferably either capable of binding to a sufficient number of binding sites on the receptor(s) and/or of binding to the receptor and sterically hindering the binding of the therapeutic agent or inducing a conformational change of the receptor, thus inhibiting binding of the therapeutic agent.
  • the atoms of the compounds must be positioned in a way that allows for the compound to exert its inhibitory effect.
  • Such inhibitory effect may result from the antagonistic binding of the compound to a receptor involved in cell toxicity and/or result from the binding of the compound to a therapeutic agent resulting in the prevention of a binding between the therapeutic agent and a receptor.
  • binding is meant a binding between the therapeutic agent and a corresponding receptor resulting in a cell toxic response.
  • the present invention relates to the use of a compound comprising a structure of the general formula (I)
  • X is a bond or a C1 -12 alkyl or a C1 -12 heteroalkyl or an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0, one, two, three or four heteroatoms, and n is an integer between 1 and 12,
  • any component of X may individually be substituted by Z, j times wherein j is an integer from 1 to 12 and wherein Z is a substituent to X of the general formula (III):
  • each substituent Z may exist in a copies wherein a is an integer from 1 to 12, wherein the optional substituents Ri, R 2 , R 3 and R 4 individually are selected from a bond to X, or a bond to R 1 , or a bond to R 2 , or a bond to R 3 , or a bond to R 4 , or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C 1-12 )-alkyl-aryl, (C 1 .
  • any of the carbons comprised by Z is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R 1 , R 2 , R 3 and R 4 can be a bond connecting to X wherein any component of X optionally may be substituted by Y, between k and I times wherein k and I are integers between O and 12 and wherein Y is a substituent described by the general formula (IV):
  • each substituent Y may exist in b copies wherein b is an integer from 1 to 12, wherein the optional substituents R 5 , R 6 , R7, Rs and R 9 individually are selected from a bond to X or a bond to R 5 , or a bond to R 6 , or a bond to R 7 , or a bond to R 8 , or a bond to R 9 , or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C 1 - 12 )-alkyl-aryl, (d- 12 )-alkoxyaryl, heteroaryl-(d- 12 )-alkyl, heterocyclyl-(d- 12 )-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carb
  • any of the carbons comprised by Y is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R 5 , R 6 , R 7 and R 8 can be a bond connecting to X, or wherein one or more of the optional substituents R 5 , R 6 , R 7 and R 8 individually or in conjunction are optionally linked to one or more of the optional substituent(s) Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and/or to N of formula III and/or to X of formula (II) and or to one of said optional substituents of said R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 thereby forming one or more rings,
  • X is a bond linking R 2 to R 5 to R 9 that may be a N linked to R 8 to R 3 thus forming a ring Q, said Q being a piperazine or piperidine ring, thereby forming the general formula V.
  • R 1 , R 4 , R 6 and R 7 are optional substituents as defined, wherein the general formula I comprises at least two amino groups individually selected from primary or secondary or tertiary amines or where the amino group optionally have a further substituent attached thus forming a quaternary ammonium,
  • the compound of the present invention wherin X of formula (II) is phenyl or cyclohexane then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or ethylamine or 2- amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or 1 ,2,2,5,5-pentamethylpyrrolidine.
  • the compound of the present invention wherin X of formula (II) is phenyl or cyclohexane, Z is not methylamine while Y is ethylamine or an amidino group or 2-amino-1 -hydroxyethyl, and Y is not methylamine while Z is ethylamine or an amidino group.
  • the compound of the present invention wherin X is C1 , then Z and Y are not both 4-aminocyclohexyl.
  • the compound of the present invention wherin Q of formula (V) is N,N'-disubstituted piperazine then the substituting groups are not N-methyl and C2- C4-alkylamine respectively or N,N-dimethyl and C2-C4-alkylamine respectively.
  • R 1 , R 4 , R 6 and R 7 are not selected among N-linked C (2 - 3) -alkylamine and a para-oriented amino group respectively, nor among N-linked hydrogen and para- oriented C (2 - 3) -alkylamine respectively.
  • X is not 2,3,4,5- tetrahydroxyhexane while Z and Y are both amine,
  • the compound of the present invention wherin X is a 1 ,4- butanediamine, Z and Y are not both 3-aminopropyl.
  • the compound of the present invention is not 3-methylamino-1 - (4-methylpiperazino)-2-propanole, 1 -(3-chlorophenyl)piperazine diHCI (m-CPP), piperazin-2-one-HCI, 2-[4-(2-aminoethyl)piperazin-1 -yl] ethylamine, piperazine anhydrous, 2,4-diamino-6-phenyl-1 ,3,5-triazine, 3,5-diamino-1 ,2,4-triazole, melonamide, arginine-HCI, piperidine, 2,5-piperazinedione, piperazine, piperazin-2- one-HCI, 1 -(2-pyrimidyl)piperazine dihydrochloride, 3-methylamino-1 -(4-methyl- piperazino)-2-propanole, 2-[4-(2-aminoethyl)piperazin-1 -yl
  • the compound of the present invention is not and the proviso that the compound is not selected from the group consisting of diaminomethane; 1 ,2- diaminoethane; 1 ,3-diaminopropane; 1 ,4-diaminobutane;
  • the compounds of the present invention do not comprise an amide group bound to a carbon. In another embodiment the compound of the present invention is not a derivative of a dimer of an original polyamine comprising an amido group.
  • each definition is independent.
  • X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure, having at least two Z-groups, and/or at least two Y-groups as selected from the general formula (II):
  • a compound is used, wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure, having 1 -3 rings, 3-8 ring members and 0 to 4 heteroatoms in each ring such as having 1 -3 rings, 5-6 ring members and 1 or 2 heteroatoms in each ring, for example having 1 -3 rings, 5-6 ring members and no heteroatoms in each ring such as having 1 -2 rings, 3-8 ring members in each and having 0 to 3 heteroatoms, , for example having 1 -3 rings, 5-6 ring members and 3-4 heteroatoms in each ring such as having 1 -2 rings, 3-8 ring members in each and having 3 to 4 heteroatoms, wherein each ring optionally is substituted j times by Z and k times by Y of the general formula (II), such as described in the below table 1 :
  • X is selected from the group consisting of cyclopentyl, furan, thiophene, pyrrole, imidazole, oxazole, and pyrrolidene, preferably the group consisting of furan and pyrrole.
  • X is selected from the group consisting of pyridine, pyrimidine, cyclohexyl, and phenyl, preferably cyclohexyl and phenyl.
  • X is an aromatic, a heteroaromatic or a 5 or 6 membered saturated ring containing 0-2 oxygen atoms, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1-12 )-alkyl, heteroaryl-(Ci_i 2 )-alkyl, heterocyclyl-(Ci_i 2 )- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, nitro, Oalkyl, Oacyl, aminoalkyl, aminopolyalkyl, alkylamin, sucrose, fructose, glucose, galacto
  • R 1 , R 2 , R 3 , R 4 of the Z- group is a C1 -12 alkyl connecting to X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 - 12 )-alkyl, heteroaryl-(d- 12 )-alkyl, heterocyclyl-(d- 12 )- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose,
  • R 5 , R 6 , R 7 , R 8 and R 9 of the Y-group is a C1 -12 alkyl connecting to X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i 2 )-alkyl, heteroaryl-(d-i 2 )-alkyl, heterocyclyl-(Ci-i 2 )- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructos
  • X is an aromatic, carbocyclic, a heterocyclic or a heteroaromatic structure having 1 ring with 6 ring members and having O to 1 heteroatoms, said ring optionally being substituted.
  • X is a dicyclohexylmethane.
  • X comprises a heterocyclic ring comprising at least one oxygen atom.
  • the compound comprises a structure of the formula VII:
  • At least one of the Y groups is H and at least one of the Y groups is OH.
  • At least one of the Z groups comprises a guanidine group.
  • a Z group comprises a guanidine group.
  • R 1 or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i 2 )-alkyl, heteroaryl-(d- 12 )- alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro,
  • R 1 or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or C3-12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i 2 )-alkyl, heteroaryl-(Ci_i 2 )- alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro,
  • Ri or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -10 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i 2 )-alkyl, heteroaryl-(Ci 2 )-alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, suc
  • R 1 or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -8 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 . 12 )-alkyl, heteroaryl-(C 1 . 12 )- alkyl, heterocyclyl-(C 1 .
  • Ri or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -6 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i 2 )-alkyl, heteroaryl-(d- 12 )- alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose
  • R 1 or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -4 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i 2 )-alkyl, heteroaryl-(Ci 2 )-alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro,
  • Ri or R 2 or R 3 or R 4 of the Z-group is a linker to X wherein said linker is a bond, or a C1 or a C2 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i 2 )-alkyl, heteroaryl-(Ci-i 2 )-alkyl, heterocyclyl-(Ci-i 2 )- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin,
  • R 1 is a C1 or C2 alkyl, substituted at least once with an imine group or substituted at least once with an OH group.
  • R 1 or R 2 or R 3 or R 4 is C1 .
  • R 1 or R 2 or R 3 or R 4 is a bond.
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i 2 )-alkyl, heteroaryl-(d-i 2 )- alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano,
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y- group is a linker to X wherein said linker is a bond, or C3-12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i 2 )-alkyl, heteroaryl-(Ci_i 2 )- alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y- group is a linker to X wherein said linker is a bond, or C1 -10 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i 2 )-alkyl, heteroaryl-(Ci-i 2 )- alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alky
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y- group is a linker to X wherein said linker is a bond, or C1 -8 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i 2 )-alkyl, heteroaryl-(Ci_i 2 )- alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, al
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -6 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i 2 )-alkyl, heteroaryl-(d-i 2 )- alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin,
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -4 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i 2 )-alkyl, heteroaryl-(Ci_i 2 )- alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alky
  • R 5 or R 6 or R 7 or R 8 or R 9 of the Y-group is a linker to X wherein said linker is a bond, or a C1 or a C2 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i 2 )-alkyl, heteroaryl-(Ci_i 2 )- alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl
  • R 1 and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl, substituted at least once with an imine group or substituted at least once with an OH group.
  • Ri and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are C1 .
  • Ri and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a bond.
  • R 1 and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a bond or a C1 -12 alkyl linker to X, said linker optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i 2 )-alkyl, heteroaryl-(Ci_i 2 )- alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy,
  • Ri and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a bond or C2-8 alkyl linker X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i 2 )-alkyl, heteroaryl-(Ci-i 2 )-alkyl, heterocyclyl-(Ci-i 2 )- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyan
  • R 1 and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a C4-6 alkyl linker to X, said alkyl being optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1 .
  • Ri and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a C1 or a C2 alkyl linker to X, said alkyl being optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C 1-12 )-alkyl, heteroaryl-(Ci_i 2 )-alkyl, heterocyclyl-(Ci_i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, triflu
  • R 1 and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl linker to X, said linker being substituted at least once with an imine group or substituted at least once with an OH group.
  • Ri and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 8 and/or R 9 of the Z-group and/or the Y-group is/are a linker C1 to X.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 of the Z-group and/or the Y-group is/are a bond.
  • R 1 is a bond and R 2 is a C1 -2 alkyl.
  • At least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 of the Z-group and/or the Y-group is/are a hydrogen.
  • At least two of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 of the Z-group and/or the Y-group are hydrogen.
  • three of Ri, R 2 , R 3 , R 4 of the Z-group and four of R 5 , R 6 , R7, Rs and R 9 of the Y-group are hydrogen.
  • At least one of R 4 , R 5 and R 6 is an hydroxyalkyl, such as hydroxyethyl.
  • Ri is linked to R 2 or R 3 or R 4 or R 5 or R 6 or R 7 or R 8 or R 9 thereby forming a ring of 5-6 members.
  • R 2 is linked to Ri or R 3 or R 4 or R 5 or R 6 or R 7 or R 8 or R 9 forming a ring of 5-6 members.
  • R 3 is linked to Ri or R 2 or R 4 or R 5 or R 6 or R 7 or R 8 or R 9 thereby forming a ring of 5-6 members.
  • R 4 is linked to Ri or R 2 or R 3 or R 5 or R 6 or R 7 or R 8 or R 9 thereby forming a ring of 5-6 members.
  • R 5 is linked to Ri or R 2 or R 3 or R 4 or R 6 or R 7 or R 8 or R 9 thereby forming a ring of 5-6 members.
  • R 6 is linked to Ri or R 2 or R 3 or R 4 or R 5 or R 7 or R 8 or R 9 thereby forming a ring of 5-6 members.
  • R 7 is linked to Ri or R 2 or R 3 or R 4 or R 5 or R 6 or R 8 or R 9 thereby forming a ring of 5-6 members.
  • R 8 is linked to Ri or R 2 or R 3 or R 4 or R 5 or R 6 or R 7 or R 9 thereby forming a ring of 5-6 members.
  • R 9 is linked to Ri or R 2 or R 3 or R 4 or R 5 or R 6 or R 7 or R 8 thereby forming a ring of 5-6 members.
  • one or more of Ri and/or R 2 and/or R 3 and/or R 4 and/or R 5 and/or R 6 and/or R 7 and/or R 9 is a guanidine group or comprises a guanidine group.
  • two of R 5 , R 6 , R 7 , R 8 and R 9 of the Y-group of formula (II) are linked to X, thereby forming one or more rings.
  • At least one of said rings has 5 members.
  • one of either R 1 or R 2 or R 3 or R 4 of the Z- group of formula (II) is linked to X and to a non-self member among R 1 , R 2 , R 3 and R 4 , thereby generating a ring of 6 members, further comprising an atomic bridge.
  • one of R 1 , R 2 , R 3 and R 4 of the Z-group of formula (II) is linked to X and to one of either R 5 or R 6 or R 7 or R 8 or R 9 of the Y- group of formula II, thereby generating a ring of 6 members, further comprising an atomic bridge.
  • R 1 and/or R 4 and/or R 6 and/or R 7 of the general formula (V) is/are unsubstituted C1 -C12 alkyl(s).
  • R 1 and/or R 4 and/or R 6 and/or R 7 of the general formula (V) is/are substituted C1 -C12 alkyl(s).
  • R 1 and/or R 4 and/or R 6 and/or R 7 of the general formula (V) is/are alkylbenzene.
  • R 1 and/or R 4 and/or R 6 and/or R 7 of the general formula (V) is/are alkylamine(s) and in yet another embodiment of the present invention said alkylamine(s) is/are unsubstituted.
  • Ri and/or R 4 and/or R 6 and/or R 7 of the general formula (V) is/are alkylamine(s) individually optionally substituted once or twice or more wherein the substituents are selected from hydrogen, O, OH, phenyl, amine (NH 2 ), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i 2 )-alkyl, heteroaryl-(Ci-i 2 )-alkyl, heterocyclyl-(Ci-i 2 )-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, alkylpolyamine,
  • R 1 and/or R 4 and/or R 6 and/or R 7 of the general formula (V) is/are H.
  • R 1 , R 4 , R 6 or R 7 of the general formula (V) is H or CH 3 .
  • R 1 , R 4 , R 6 or R 7 of the general formula (V) is a primary, secondary, tertiary or quaternary amine or a secondary, tertiary or quaternary d- ⁇ -alkylamine.
  • X is a bond connecting R 2 and R 5 of the general formulas (N-IV).
  • X is a bond connecting R 2 of the Z-group of formula (II) and R 5 of the Y-group of formula I and none of R 1 , R 3 , R 4 , and R 6 R 7 , R 8 is linked to another substituent R 1 -R 8 .
  • R 2 of the general formula (III) is a bond linked to X of the general formula (II) and R 5 of the general formula (III) is C1 -12 alkyl substituted at least once with an OH group.
  • R 2 of the general formula (III) is C4 alkyl substituted two, three or four times with an OH group.
  • one, two or three or all of R 3 , R 4 , R 5 , and R 6 of the general formulas (III-IV) are hydrogen.
  • the compound of the general formula (I) has a polybasic charge distribution.
  • the compound of the general formula (I) has at least two positively charged nitrogens under physiological conditions wherein said positively charged nitrogens are separated by 2-1 OO atoms, such as 2-3 atoms, e.g. 3-4 atoms, such as 3-4 atoms e.g. 4-5 atoms, such as 5-6 atoms e.g. 6-7 atoms, such as 7-8 atoms, e.g.8-9 atoms, suchas 9-10 atoms, e.g. 10-1 1 atoms, such as 1 1 -12 atoms, e.g. 12-13 atoms, such as 13-14 atoms, e.g.
  • 14-15 atoms such as 15- 16 atoms, e.g. 16-17 atoms, such as 17-18 atoms, e.g. 18-19 atoms, such as 19-20 atoms, e.g. 20-25 atoms, such as 25-30 atoms, e.g. 30-35 atoms, such as 35-40 atoms, e.g. 40-45 atoms, such as 45-50 atoms, e.g. 50-55 atoms, such as 55-60 atoms, e.g. 60-65 atoms, such as 65-70 atoms, e.g. 70-75 atoms, such as 75-80 atoms, e.g. 80-85 atoms, such as 85-90 atoms, e.g. 90-95 atoms, such as separated by 95-100 atoms.
  • the compound of the general formula (I) does not comprise a substituted or unsubstituted piperazine or piperidine structure.
  • the compound does not comprise a ring structure having 3 nitrogen atoms.
  • the compound of the general formula (I) is capable of binding to the receptor megalin and/or the receptor cubilin.
  • the compound or combination of compounds of the present invention is/are selected from the group consisting of 2,4 Diamino-6-hydroxypyrimidine; 2-Phthalimido acetamide; 1 -(3-chlorophenyl)piperazine; 1 -(3-chlorophenyl)piperazine hydrochloride; 3,6-diaminoacridin sulphate (proflavin); 3,7-diaminoanthraquinone; 1 ,4-diaminobenzene; 4,4'diaminobiphenyl; 1 ,8-diamino-4,5-dihydroxyanthraquinone; 2,5-diamino2,5-dimethylhexane; 3,3'diaminodipropylamine; 3,3'diaminodipropylamine;
  • Adipic acid dihydrazide 1 ,1 -Hexamethylenebis(5-(4-chlorophenyl)biguanide) hexa hydrochloride (Chlorhexidine); 2,2'-(2-(3,4,5-trimethoxyphenyl)piperazine-1 ,4- diyl)diethanamine; L-Lysine hydroxamate hydrochloride; Bis-(6-aminohexyl)-amine; 4-(aminomethyl)benzamide; 2,2'-(1 ,4-diazepane-1 ,4-diyl)diethanamine tetrahydrochloride; 2,2'-(2-phenylpiperazine-1 ,4-diyl)diethanamine tetrahydrochloride;
  • Suberohydroxamic acid L-Arginine hydroxamate hydrochloride; (2R,3r,4S)-1 ,5- diaminopentane-2,3,4-triol dihydrochloride; N,N'-dihydroxy-1 ,4-Benzenedicarboxamide; 3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)dipropanoic acid;
  • Dopamine hydrochloride 1 -phenylethylpiperazine; 1 -(4-methoxyphenyl)-Piperazine dihydrochloride; N-(2-hydroxyethyl)piperazine; 3-amino-4-hydroxybenzhydrazide;
  • the compounds of the present invention are selected from the group consisting of Bis-(6-aminohexyl)-amine; 2,2'-(2-phenylpiperazine-1 ,4- diyl)diethan amine tetrahydrochloride;
  • the compounds of the present invention are selected from the group consisting of Trans 2,2'-(cyclohexane-1 ,4-diyl)diethanamine dihydrochloride; Polypropylenimine-tetraamine Dendrimer; Tris-(2-aminoethyl)-amine; N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 - diyl))dipropane-1 ,3-diamine; N1 ,N1 '-(pyridine-2,6-diylbis(methylene))dipropane-1 ,3- diamine pentahydrochloride and 2,2'-(1 ,4-phenylenebis(sulfanediyl))diethanamine di hydrochloride.
  • the compounds of the present invention are selected from the group consisting of 3,3'-(piperazine-1 ,4-diyl)dipropan-1 -amine tetrahydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(4-aminobutyl)butane- 1 ,4-diamine) hexahydrochloride; N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 - diyl))bis(N1 -(2-aminoethyl)ethane-1 ,2-diamine) octa hydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(2-aminoethyl)ethane-1 ,2-diamine) hexa hydrochloride;
  • the present inventors have found a correlation between the structural arrangement of the compounds of the present invention and their efficacy as inhibitors of aminoglycoside uptake in the kidneys through the receptors megalin and cubilin.
  • the inventors have also discovered that the toxic effect may be avoided through optimizing the orientation and distance between amino groups and other electron rich elements of the compounds of the present invention.
  • the compounds of the present invention are selected from the group consisting of a) Compounds that contain at least one, preferably at least two, non-cyclic alkyl- amine group(s), wherein said alkyl amine groups may be substituted as described herein (above). b) Alkyl-amine deficient group(s) that are not part of ring structures.
  • Examples of a) include but are not limited to RC029, RC030, RC032, RC037, RC038, RC040, RC088, RC091 , RC092, RC093, RC094, R095, RC096,
  • Examples of b) include but is not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC057, RC089, RC090, RC101 , RC102, RC104, RC1 10, RC128, RC129, RC130, RC136, RC138, RC139, RC140, RC141 , RC142, RC143, RC147, RC148, RC151 , RC152, RC154, RC155, RC156, RC158, RC162,
  • the compounds of the present invention are selected from the group consisting of a) Compounds that contain one or more guanidine groups or at least one, preferably at least two, alkyl-amine group(s), that are not part of a ring structure wherein said alkyl amine groups may be substituted as described herein above.
  • Examples of a) include but are not limited to RC029, RC030, RC032, RC037,
  • RC224 RC225, RC226, RC227, RC227-1 , RC228, RC229, RC230, RC231 , RC233, RC234, RC235, RC236, RC237, RC238, RC239, RC240, RC241 , RC242, RC243, RC244, RC245, RC246, RC247, RC248, RC249, RC250, RC251 , RC252, RC253, RC254, RC255, RC256, RC257, RC258 (of figure 1 ), and analogues thereof.
  • Examples of b) include but is not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC057, RC089, RC090, RC101 , RC104, RC1 10, RC128, RC129, RC130, RC136, RC138, RC139, RC140, RC141 , RC142, RC143, RC147,
  • the efficacy of the compounds of the present invention to act as inhibitors of aminoglycoside uptake is dependant on the number of, and distance between the non- cyclic alkyl-amine groups comprised by the general formula (II). Accordingly, in one embodiment, the compounds of the present invention are selected from the group consisting of
  • Examples of a) include but are not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC057, RC089, RC090, RC101 , RC102, RC104, RC1 10, RC1 16, RC128, RC129, RC130, RC136, RC138, RC139, RC140, RC141 , RC142,
  • Examples of b) include but are not limited to RC032, RC094, RC1 16, RC126, RC131 , RC132, RC135, RC137, RC146, RC149, RC150, RC153, RC159, RC161 , RC166, RC171 , RC172, RC173, RC179, RC196, RC217, RC218, RC219, RC234, RC236, RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC247, RC248, RC255, RC256, RC257 (of figure 1 ) and analogues thereof.
  • Examples of c) include but are not limited to RC029, RC037, RC038, RC040, RC088, RC091 , RC092, RC095, RC096, RC100, RC103, RC105, RC106,
  • Examples of d) include but are not limited to RC030, RC093, RC097, RC1 12, RC1 14, RC1 15, RC1 18, RC1 19, RC120, RC124, RC134, RC144, RC145, RC174, RC188, RC190, RC191 , RC192, RC193, RC194, RC195, RC198, RC200, RC201 , RC202, RC203, RC204, RC207, RC208, RC210, RC212, RC213, RC214, RC215, RC216, RC220, RC222, RC223, RC224, RC225,
  • the compounds of the present invention comprise three or more non- cyclic amines in unbranched non-cyclic alkyl chains. Examples thereof include but are not limited to RC030, RC093, RC097, RC1 14, RC1 15, RC1 18, RC1 19, RC120, RC124, RC194, RC195, RC200, RC208, RC215, RC216, RC222, RC224, RC226, RC229, RC233, RC251 , RC252, RC254 (of figure 1 ) and analogues thereof.
  • the compounds of the present invention comprise three or more non- cyclic amines in branched alkyl chains. Examples thereof include but are not limited to RC1 12, , RC134, RC144, RC145, RC174, RC188, RC190, RC191 , RC192, RC193, RC198, RC201 , RC202, RC203, RC204, RC207, RC210, RC212, RC213, RC214,
  • the compounds of the present invention are dependent on the nature of the spacer region X of the general formula (II). Accordingly, in one embodiment, the compounds of the present invention are selected from the group consisting of: a) cyclic structures, and b) non-cyclic structures.
  • Examples of a) include but are not limited to RC001 , RC006, RC014, RC014-1 RC023, RC024, RC025, RC026, RC028, RC031 , RC032, RC033, RC034, RC035, RC036, RC056, RC057, RC088, RC090, RC091 , RC094, RC095, RC096, RC104, RC105, RC106, RC107,
  • RC158 RC159, RC160, RC161 , RC162, RC163, RC164, RC165, RC166, RC168, RC169, RC170, RC171 , RC172, RC173, RC174, RC176, RC178, RC179, RC181 , RC182, RC183, RC184, RC185, RC186, RC188, RC189, RC190, RC191 , RC192, RC196, RC199, RC200, RC202, RC203, RC204, RC205, RC206, RC207, RC208,
  • RC210 RC21 1 , RC212, RC213, RC215, RC216, RC217, RC218, RC219, RC221 , RC222, RC223, RC224, RC225, RC226, RC227, RC227-1 , RC228, RC229, RC230, RC231 , RC234, RC235, RC236, RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC246, RC248, RC250, RC251 , RC252, RC253, RC254, RC255,
  • Examples of b) include but are not limited to RC029, RC030, RC037, RC038, RC040, RC089, RC090, RC091 , RC092, RC093, RC097,
  • cyclic structures are selected from the group consisting of a) non aromatic cyclic structures, and b) aromatic cyclic structures.
  • Examples of a) include but are not limited to RC032, RC057, RC088, RC091 , RC095, RC109, RC1 17, RC1 18, RC123, RC125, RC127, RC130, RC136, RC147, RC164, RC173, RC178, RC179, RC186, RC188, RC196, RC199, RC217, RC219, RC221 , RC222, RC223, RC224, RC228, RC231 , RC253, RC254, RC255, RC256, RC257,
  • Examples of b) include but are not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC090, RC094, RC096, RC105, RC106,
  • X of the general formula (II) in said non-cyclic structures is an alkyl structure.
  • examples thereof include but are not limited to RC029, RC030, RC037, RC038, RC040, RC089, RC090, RC091 , RC092, RC093, RC097, RC100, RC101 , RC102, RC103, RC1 14, RC1 15, RC1 19, RC120, RC124, RC180, RC193, RC194, RC195, RC197, RC198, RC201 , RC209, RC214, RC220, RC233, RC239, RC247, RC249 (of figure 1 ), and analogues thereof.
  • the compounds of the present invention comprises piperazines with two symmetrically placed alkyl amine chains and optionally one more substituent on the piperazine. Examples thereof include but are not limited to RC088, RC091 , RC096, RC1 13, RC121 , RC122, RC123, RC125, RC127, RC188,
  • the compounds of the present invention comprises piperazines and diazepanes with two alkyl amine chains and optionally one more substituent on the piperazine or diazepane.
  • Examples thereof include but are not limited to RC088, RC091 , RC095, RC096, RC1 13, RC121 , RC122, RC123, RC125, RC127, RC188, RC222, RC223, RC224, RC228 (of figure 1 ), and analogues thereof.
  • the compounds of the present invention comprises piperazines with two asymmetrically placed alkyl amine chains and optionally one more substituent on the piperazine.
  • Examples thereof include but are not limited to RC1 16, RC166, RC223, RC228, RC231 , RC253, (of figure 1 ), and analogues thereof.
  • the compounds of the present invention comprises piperazine compounds comprising more than 4 amines.
  • examples thereof include but are not limited to RC188, RC189, RC222, RC223, RC224, RC228, RC231 , RC253 (of figure 1 ), and analogues thereof.
  • the compounds of the present invention comprises small benzene containing compounds and saturated analogues.
  • examples thereof include but are not limited to RC025, RC032, RC094, RC104, RC109, RC126, RC128, RC131 , RC132, RC137, RC138, RC139, RC140, RC141 , RC142, RC143, RC145, RC148, RC149, RC150, RC151 , RC152, RC153, RC154, RC155, RC156, RC157, RC158, RC159, RC160, RC161 , RC162, RC163, RC165, RC172, RC182, RC183, RC184, RC185, RC210, RC234, RC235, RC236, RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC248, RC255,
  • the compounds of the present invention comprises large unbranched compounds containing aromatic rings, and two identical substituents on the ring.
  • examples thereof include but is not limited to RC106, RC200, RC208, RC215, RC216, RC226, RC229, RC250, RC251 , RC252, RC254, RC258 (of figure 1 ), and analogues thereof.
  • the compounds of the present invention comprises large branched compounds containing aromatic rings.
  • examples thereof include but is not limited to RC107, RC134, RC144, RC174, RC189, RC190, RC191 , RC202, RC203, RC204, RC205, RC206, RC207, RC210, RC21 1 , RC212, RC213, RC225, RC227, RC230 (of figure 1 ), and analogues thereof.
  • X of formula (II) of the compounds of the present invention comprises unbranched aliphatic compounds.
  • examples thereof include but are not limited to RC030, RC030-1 , RC093, RC101 , RC102, RC1 10, RC1 14, RC1 15, RC1 19, RC120, RC124, RC147, RC194, RC195, RC209, RC233, RC239 of figure 1 , and analogues thereof.
  • X of formula (II) of the compounds of the present invention comprises branched aliphatic compounds. Examples thereof include but are not limited to RC032, RC038, RC109, RC1 12, RC192, RC193, RC197, RC198, RC201 , RC221 of figure 1 , and analogues thereof.
  • the compounds of the present invention comprises aminoglycoside fragments.
  • An example thereof include but is not limited to RC179 of figure 1 , and analogues thereof Novel Polymers
  • the compound structure is a multimer of monomeric compounds individually defined by the general formula (I).
  • the compound is of the general formula (IX)
  • A is independently selected from formula (I) and/or formula (II) and/or formula
  • D is a spacer, q is an integer of 1 -100, p is an integer of 1 -100.
  • said spacer may be a covalent bond, wherein said spacer may consist of from 2-12 atoms, such as C-atoms, for example from 4-10 atoms, such as C-atoms, preferably from 6-8 atoms, such as C-atoms.
  • the compound of the general formula (I) is a pharmaceutically acceptable addition salt or hydrate of said compound, such as but not limited to bromide, chloride, fluoride, hydride, iodide, nitride, oxide, phosphide, sulfide, peroxide, borate, bromate, hypobromite, carbonate, hydrogen carbonate, bicarbonate, chlorate, perchlorate, chlorite, hypochlorite, chromate, iodate, nitrate, nitrite, phosphate, hydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, thiosulfate, hydrogen sulfate, bisulfate, sulfite, hydrogen sulfite, bisulfite, acetate, formate, oxalate, hydrogen oxalate, bioxalate, hydrogen sulfide, bisulfide, telluride, amide, thio
  • Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like.
  • the compounds according to the invention are capable of accepting at least one proton, more preferably at least two protons because the structure of such compounds allows cell toxicity inhibition to be manifested.
  • the compounds preferably have at least one amino group or one guanidino group capable of functioning as a proton acceptor. More preferably, the compounds have two amino groups capable of functioning as a proton acceptor.
  • the present compound has at least 1 , such as 2 positive charges in solution at physiological pH (i.e. pH 7.4), such as at least 2 positive charges.
  • the compound has at least 2 positive charges, preferably at least 2 positively charged nitrogens, under physiological conditions.
  • the polybasic charge distribution has the same charge distribution as the cell toxicity inducing therapeutic agent.
  • a plausible explanation why a polybasic charge distribution is advantageous may be that the binding of the aminoglycoside gentamicin to the receptor(s) is not necessarily dependent on the native conformation of the receptor, since reduction of disulfide-bridges does not significantly interfere with ligand binding. Moreover, the addition of EDTA, which depletes the presence of calcium and affects receptor stability, does not abolish binding. This indicates that the interaction between receptor and gentamicin may depend on simple ionic interactions rather than the overall conformation of the receptor.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined herein or a compound for which a use is described herein and pharmaceutically acceptable carriers, excipients or diluents therefore.
  • a compound is used for the preparation of a medicament for the prophylaxis and/or treatment of nephrotoxicity and/or ototoxicity wherein the stoichiometric ratio between a compound p and a salt q
  • p may be any integer from 0 to 100 and wherein q may be any integer Q from O to 100.
  • a combination medicament comprising a compound as defined above and a therapeutic agent that may be an antibiotic agent, for simultaneous, separate or sequential use in therapy.
  • a pharmaceutical composition comprising a compound as defined above and pharmaceutically acceptable carriers, excipients or diluents therefor.
  • the compounds as defined herin above comprise any stereochemical variation or combination thereof of the compound defined by the general formula I.
  • the compound L of formula I is present singularly, plurally or as a combination thereof as selected from the compounds defined herein above.
  • the dosage of the compound according to the present invention depends on the compound in question; however, the amount of the compound is also closely related to the therapeutic agent co-administered with the compound as well as the dosage of said therapeutic agent.
  • the daily oral dosage regimen will preferably be from about 0.1 ng/kg of total body weight to about 10 g/kg of total body weight, such as 0.1 ng/kg of total body weight, for example 0.5 ng/kg of total body weight, such as 1 ng/kg of total body weight, for example 5 ng/kg of total body weight, such as 10 ng/kg of total body weight, for example 50 ng/kg of total body weight, such as 100 ng/kg of total body weight, for example 200 ng/kg of total body weight, , such as 300 ng/kg of total body weight, for example 400 ng/kg of total body weight, such as 500 ng/kg of total body weight, for example 600 ng/kg of total body weight, such as 700 ng/kg of total body weight, for example 800 ng/kg of total body weight, such as 900 ng/kg of total body weight, for example 1 ⁇ g/kg of total body weight, such as 2 ⁇ g/kg of total body weight
  • the daily parenteral dosage regimen will be from about 0.001 to about 500 mg/kg of total body weight, preferably 0.01 -350 mg/kg, more preferably 0.1 - 200 mg/kg, such as 0.1 -100 mg/kg of total body weight.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a compound, alone or in combination with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle.
  • the specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host.
  • the dose administered should be an "effective amount” or an amount necessary to achieve an "effective level" in the individual patient.
  • Effective level which is the goal of the employed dose, is defined as the concentration of the compound necessary to obtain the desired effect of using said compound.
  • Such “effective level” may refer to the concentration of the compound in the blood, the plasma, the serum, the urin, the extracellular fluid, or in the target organ, such as the kidney or the inner ear.
  • the “effective level” may be directly measurable using any method of analysis of compound concentration familiar to a person skilled in the art, but it may also be indirectly measured as the level obtained after dispensing a drug dose that is adequate to obtain the desired result.
  • the ratio of the compound administered to the therapeutic agent administered is in the interval of from 200:1 mokmol to 1 :200 mokmol, such as in the interval of from 150:1 to 1 :150 mokmol, such as in the interval of from 100:1 mokmol to 1 :50 mokmol, such as in the interval of from 50:1 mokmol to 1 :25 mokmol, such as in the interval of from 25:1 to 1 :200 mokmol, such as in the interval of from 10:1 to 1 :200 mokmol, such as in the interval of from 5:1 to 1 :200 mokmol, such as in the interval of from 25:1 to 1 :100 mokmol, such as in the interval of from 10:1 to 1 :100 mokmol, such as in the interval of from 5:1 to 1 :100 mokmol, such as in the interval of from 25:1 to 1 :50 mokmol, such as in the interval of from 10:1 to 1 :50 mokmol, such as in the interval of from
  • the compound may be administered in any suitable dosage regime, but is preferably administered with the same intervals as the therapeutic agent, preferably either shortly before or during administration of the therapeutic agent.
  • the compound according to the invention may be administered in any suitable manner according to the formulation thereof, it the compound is administered parenterally, such as intravenously as the therapeutic agent.
  • the present medicament is capable of binding to the receptor megalin.
  • the medicament is capable of binding to the receptor cubilin.
  • the medicament is capable of binding to a co- receptor of megalin and cubilin.
  • the medicament is capable of binding to a therapeutic agent capable of binding to the receptor megalin and/or the receptor cubilin and/or a co- receptor of megalin and cubilin.
  • compounds of the present invention are utilised to prevent the uptake or salvaging of circulating polyamines by rapidly proliferating cells such as tumour cells, in order to potentiate the effect of therapeutic inhibitors of polyamine biosynthesis.
  • Combination medicaments The present invention further relates to a combination medicament comprising the compound according to the invention in combination with a therapeutic agent.
  • the invention further relates to a combination medicament comprising a compound as disclosed by the invention or a compound for which a use is described herein and a therapeutic agent for simultaneous, separate or sequential use in therapy, preferably antimicrobial therapy.
  • the therapeutic agent is any one of the above- mentioned agents.
  • the goal of the administration is to achieve an effective systemic level of the compound. In one embodiment of the invention this may be achieved by simultaneous administration of the compound and the medicament. In another embodiment of the present invention this may be achieved by separate administration of the compound and the medicament.
  • the time interval between the administrations may preferably be from 0 - 30 minutes, or from 0-15 minutes, or from 0-5 minutes or even more preferably from 0 - 2 minutes or from 0 -1 minute.
  • the main routes of drug delivery according to the present invention are intravenous, oral, and topical, as will be described below. Other drug administration methods, such as subcutaneous injection, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
  • Compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds may also be administered by inhalation, such as by intranasal and oral inhalation administration.
  • the mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the mammal to which the biologically active compound is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • the parenteral formulations of the present invention will typically contain from about 0.05 to about 25% by weight of the active ingredient in solution, such as 0.1 to about 25% by weight of the active ingredient in solution, such as 0.2 to about 25% by weight of the active ingredient in solution, such as 0.3 to about 25% by weight of the active ingredient in solution, such as 0.4 to about 25% by weight of the active ingredient in solution, such as 0.5 to about 25% by weight of the active ingredient in solution, such as 0.6 to about 25% by weight of the active ingredient in solution, such as 0.7 to about 25% by weight of the active ingredient in solution, such as 0.8 to about 25% by weight of the active ingredient in solution, such as 0.9 to about 25% by weight of the active ingredient in solution, such as 1.0 to about 25% by weight of the active ingredient in solution, such as 2.0 to about 25% by weight of the active ingredient in solution, such as 3.0 to about 25% by weight of the active ingredient in solution, such as 4.0 to about 25% by weight of the active ingredient in solution, such as 5.0 to about 25% by weight of the active ingredient in solution, such as
  • compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the medicament is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration or inhalation.
  • said injection of said medicament is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
  • the duration of the medication is between 30 minutes to 24 hours.
  • the duration of the medication is between 1 to 6 hours.
  • the duration of the medication is from 6 to 72 hours.
  • the duration of the medication is from 1 to 14 days.
  • the duration of the medication is from 4 to 10 days.
  • the duration of the medication is from 10 to 30 days. In another embodiment of the present invention the duration of the medication is from 15 to 25 days.
  • the compounds of the present invention may all be capable of binding to the receptor megalin and/or the receptor cubilin and/or a co-receptor of megalin and cubilin. Additionally the compounds according to the invention may be capable of binding to the therapeutic agent. In case of binding to the receptor(s) it is of importance that the binding is effective in respect of blocking the binding of the therapeutic agent to the receptor.
  • the receptor megalin for example comprises 50-150 binding sites for the therapeutic agent gentamicin and it is important for the effectiveness of the use of this invention that the compound is capable of inhibiting an effective amount of these binding sites.
  • the advantage of the present compound's ability of binding to the receptor cubilin and/or receptor megalin is the finding that these receptors are involved in aminoglycoside induced cell toxicity in the kidneys and the ear.
  • Using the present compounds has an inhibitory effect on cell toxicity, such as nephrotoxicity and ototoxicity.
  • the compounds according to the invention may e.g. bind the receptor megalin in order to inhibit endocytosis or the receptor cubilin in order to reduce its sequestering and thereby inhibiting or reducing endocytosis.
  • the compound may bind to a co-receptor of megalin and cubilin.
  • the therapeutic agent according to the invention may be any therapeutic agent capable of causing organ damages due to intracellular accumulation in cells in the organs.
  • the therapeutic agent is capable of accumulating in cells in the kidneys and/or inner ear, thus causing kidney damages as well as damages to the inner ear.
  • the induced cell toxicity is a side-effect of a therapeutic agent, wherein the therapeutic agent is selected from acebutolol, acetazolamide, acyclovir, adefovir, albumin, alclofenac, alendronate, alitretinoin, altretamine, amikacin, amiloride, aminoglutethimide, amiodarone, amoxicillin, amoxicillin/clavulanic acid, amphotericin b, amphotericin b cholesteryl sulfate complex, amphotericin b lipid complex, amphotericin b liposome, amtolmetin, aniracetam, antacids, antazoline, anthraquinone laxatives, aprotinin, arbekacin, arginine, arsenic trioxide, asparaginase, aspirin, atenolol, atovaquone
  • the induced cell toxicity is a side-effect of a therapeutic agent, wherein the therapeutic agent is selected from the group consisting of aminoglycosides, such as arbekacin, gentamicin, kanamycin, neomycin, paramycin, ribostamycin, lividomycin, amikacin, dibekacin, butakacin, tobramycin, streptomycin, dihydrostreptomycin, sisomicin, verdamicin, netilmicin, and butikacin; cisplatin, amphotericin B, ifosfamide, polymyxin B, cyclophosphomide, methotrexate, aprotinin, ciclosporin, and valproate as well as therapeutic antibodies.
  • aminoglycosides such as arbekacin, gentamicin, kanamycin, neomycin, paramycin, ribostamycin, lividomycin, amikacin, dibekacin
  • the therapeutic agent is an aminoglycoside, such as gentamicin, arbekacin or kanamycin.
  • fusion proteins or fusion products used for medical treatment wherein one of the proteins is capable of binding the megalin or the receptor cubilin and/or a co-receptor of megalin and cubilin and the other protein/product causes cell toxicity when accumulating in the cells, may be used.
  • fusion products wherein one part of the product is an antibody or IgG light chain, both capable of unspecifically binding to cubilin, and the other part of the product is cytotoxic, such as cancer treatment, may be co-administered with a compound according to the present invention in order to reduce organ damage, in particular kidney damage.
  • the therapeutic agent causing nephrotoxicity and/or ototoxicity is an aminoglycoside.
  • the compounds of the present invention are used for treatment of cancer other than leukemia or breast cancer. Examples
  • Example 1 Mice were injected intravenously with doses (5 mg/kg) of gentamicin with or without 4 ⁇ g RC1 12. After 120 minutes, the animals were sacrificed and the kidneys removed. The amount of 3 H-gentamicin accumulating in the tissues was determined and expressed as % of total tracer injected. The results are illustrated in figure 2.
  • Example 2 Male mice (e.g. 83 SPF BomTac:NMRI from Taconic Europe A/S) were used for the experiments. After acclimatization the animals were approximately 5 weeks old. They were fed a diet of Altromin 1314 Fortified and had free access to drinking water. Mice were injected intravenously with a relevant dose of antagonist in PBS (volume 0.2 ml) followed by an intravenous injection with a mixture of 3H labelled gentamicin (GE Healthcare) and 5 mg/kg cold gentamicin (volume 0.2 ml, approx 10,000,000 cpm/ml, the dose of cold gentamicin corresponds to a clinical relevant dose for humans) .
  • PBS volume 0.2 ml
  • 5 mg/kg cold gentamicin volume 0.2 ml, approx 10,000,000 cpm/ml, the dose of cold gentamicin corresponds to a clinical relevant dose for humans
  • a control group was administered PBS without antagonist prior to gentamicin administration. After 24 hours, the animals were sacrificed and the kidneys removed. The amount of 3H-gentamicin accumulating in the kidney tissue was determined. Inhibition of gentamicin uptake was expressed as percentage reduction compared to the control group. The number of animals per group was at least 3 in all experiments. Results are displayed for selected compounds in table 2 below.
  • Example 3 In vitro testing of compounds Gentamicin-inhibitor interactions were assessed by surface plasmon resonance (SPR) analysis on a Biacore 2000 instrument (Biacore, Uppsala, Sweden). Megalin purified from rabbit kidneys as described in Birn et al. (J. Biol. Chem., 1997, Vol. 272, No. 42, 26497-26504) was immobilized in a concentration of 28-40 fmol/mm 3 . Samples were dissolved in 10 mM Hepes, 150 mM NaCI, 1.5 mM CaCI2, 1 mM EGTA, 0.005 % Tween-20 pH 7.4. The same buffer was used as running buffer.
  • SPR surface plasmon resonance
  • Re-generation of the sensor chip after each analysis cycle was performed with 1 .6 M glycine-HCI buffer pH 3.0.
  • the Biacore response is expressed in relative response units (RU) i.e. the difference in response between protein and control flow channel.
  • Samples contained 1 mM gentamicin and 0-10 mM or 0-20 mM inhibitor. The response was read at maximum and corrected for contribution of the inhibitor response.
  • the experiment examines the inhibiting effect of comounds of the present invention. The results are displayed in figure 1 .
  • Examples of compounds used in the invention are also displayed, if present are inhibition of gentamicin binding to immobilized megalin as assessed by surface plasmon resonance.

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Abstract

The present invention relates to the use of compounds for the manufacture of a medicament for the prophylaxis and/or treatment of induced cell toxicity, such as nephrotoxicity and ototoxicity, in particular where the cell toxicity is induced by a medical treatment. In an embodiment, the compounds have at least two nitrogen atoms, more preferably at least two amino groups. The compounds according to the invention are capable of blocking binding of cell toxic compounds to the megalin receptor, and thereby inhibiting uptake of the cell toxic compounds into cells. The invention further relates to novel compounds for use in said treatment, as well as a method for reducing the cell toxicity of cell toxic compounds.

Description

Prevention of nephrotoxicity III
All patent and non-patent references cited in the present application are hereby incorporated by reference in their entirety.
Field of invention
The present invention relates to the technical field of cell toxicity treatment and discloses compounds and combination medicaments for use in such treatment.
Background of invention
The invention relates to compounds for the prevention of organ damage, in particular organ damage of the kidneys and the inner ear induced by the administration of therapeutic agents.
Several classes of drugs in clinical use are toxic to tissues like the kidney and inner ear. Prominent drugs in this category are cisplatin, ifosfomide, cyclosporine, amphotericin B, valproate, polymyxin B and therapeutic antibodies. However, of particular importance are aminoglycosides which are among the most important antibiotics for the treatment of severe bacterial infections. They are the preferred agents against a number of Gram-negative bacteria. Above all, this is due to a general increase in the occurrence of pathological strains resistant to other classes of antibiotics. This may positively influence the market share of aminoglycosides.
The main obstacle in the clinical use of the above drugs is their severe oto- and nephrotoxic (ear and kidney) side effects, which may lead to complete loss of hearing and to renal failure. The use of these drugs is thus not only associated with a high risk but also entails high costs for drug monitoring and diagnosis. Their use is therefore restricted to incidences of the most severe infections in the industrial countries. In the developing countries, where aminoglycosides are used more frequently because of their low production costs, aminoglycosides account for 70% of all cases of acquired deafness. The underlying mechanisms causing toxicity are not understood. So far it is known that the drugs bind to the surface of cells in the kidneys and the inner ear and are taken up into the cells through unknown mechanisms. As the drugs are poorly degradable in the cells, they accumulate intracellular^ leading to the destruction of cell structures and thus to renal damage and hearing loss. Various surface structures or receptors have been held responsible for the binding and uptake of the antibiotics.
Moestrup et al. suggested that megalin, a surface receptor of the kidneys, is responsible for the uptake of antibiotics (Moestrup et al., J. CIIn. Invest. 96, 1404-1413, 1995). Megalin is a 600 kDa endocytosis receptor of the low-density lipoprotein (LDL) receptor gene family. Megalin is a multifunctional clearance receptor that binds and internalises a number of macromolecules. The sequence for megalin is shown as: cDNA: U33837; gene: NT_002176.
Another receptor believed to be involved in antibiotic interaction is cubilin. Cubilin is a 460 kDa membrane-associated protein colocalizing with megalin, which may facilitate the endocytic process by sequestering the antibiotic/therapeutic agent on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. In other words, the therapeutic agent may bind to cubilin as well as directly to megalin. Cubilin, however, appears not to be able to mediate endocytosis on its own but physically associates with megalin and internalizes in a complex with this receptor. The sequence for cubilin is shown as: cDNA: XM 01 1904; gene: NT 008682 (Homo sapiens chromosome 10 working draft sequence segment).
Several strategies for preventing toxic side effects of aminoglycosides have been developed. Examples are the development of novel aminoglycosides having fewer side effects (see amikacin, a semi-synthetic derivative of kanamycin (Begg, EJ. & Barclay, M. L. Br. J. CHn. Pharmac. 39, 597-603, 1995)), and the simultaneous administration of aminoglycosides with other compounds, such as neurotrophin-3 (Ernfors, P., Duan, M.L., EIShamy, W.M. & Canlon, B. Nat. Med. 2, 463-467 (1996)), nitrendipine (Lee, S.M., Pattison, M.E. & Michael, U. F. J. Cardiovasc. Pharmacol. 9, S65-S69 (1997)), Pyrola rotundifolia (Xuan, W. & Dong, M. Ann. Otol. Rhinol. Laryngol. 104, 374-380 (1995)), antioxidants (Schacht, J. Head and Neck Surgery 118, 674-677 (1998)), or, for ototoxicity, guanidine-analogs (WO 99/02145) . In Jones et al. (Jones, M. M., Basinger, M.A., and Holscher, M.A.; Fundamental and applied toxicology, 18, 181 -188 (1992)) the control of nephrotoxicity and/or ototoxicity of cisplatin by clinically using sulphur-containing compounds is described. Jones et al. disclose how sulphur-containing compounds bind to hydrolytic products derived from the platin part of cisplatin and thereby reduce the nephrotoxic side effect of cisplatin.
The article does not disclose cell toxicity reducing compounds or medicaments capable of binding to a receptor cubilin and/or a receptor megalin and/or a co-receptor of megalin and cubilin.
Summary of invention
The present invention relate to use of a compound comprising a structure of the general formula (I):
[L]m
wherein m is an integer between 1 -100, for example 1 -50, such as 1 1 -20, for example 1 -10, and L is of the general formula (II):
aZ: (X) — bYk
wherein X is a bond or a C1 -12 alkyl or an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyl comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O)0-2 or carbonyl, and
wherein n is an integer between 1 and 12, and
wherein any component of X may individually be substituted with Z, j times wherein j is an integer from 1 to 12 and wherein Z is a substituent to X of the general formula
and wherein each substituent Z may exist in a copies wherein a is an integer from 1 to 12, wherein the optional substituents Ri, R2, R3 and R4 individually are selected from a bond to X, or a bond to R1, or a bond to R2, or a bond to R3, or a bond to R4, or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C1-12)-alkyl-aryl, (d-12)-alkoxyaryl, heteroaryl-(d-12)-alkyl, heterocyclyl-(C1.12)-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, guanidino, nitro, O-alkyl, O-acyl, hydroxyalkyl, aminoalkyl, aminopolyalkyl, alkylamin, sucrose, fructose, glucose, galactose, maltose, lactose, mannose or wherein R1 is a hydrogen, R2 is 1 -imino- aminomethyl and R3 , selected from any of the above, connecting the thus formed guanidino group to X, wherein any of the substituents R1, R2, R3 or R4, optionally may be substituted individually at least once, wherein the substituents are selected from: hydrogen, O, OH, phenyl, amine (NH2), imine (NH), aminoalkyl, aminopolyalkyl, alkylamin, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.12)-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1.12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, guanidino, nitro, sucrose, fructose, glucose, galactose, maltose, lactose or mannose, wherein at most 50% of the carbons comprised by Z is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R1, R2, R3 and R4 can be a bond connecting to X wherein any component of X optionally may be substituted with Y, k times wherein k is an integer between O and 12 and wherein Y is a substituent described by the general formula (IV): R6
K5 Hg ^~^~ Ky
R8
and wherein each substituent Y may exist in b copies wherein b is an integer from 1 to 12, wherein the optional substituents R5, R6, R7, Rs and R9 individually are selected from a bond to X or a bond to R5, or a bond to R6, or a bond to R7, or a bond to R8, or a bond to R9, or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (d-i2)-alkyl-aryl, (d-i2)-alkoxyaryl, heteroaryl-(Ci_ i2)-alkyl, heterocyclyl-(d-i2)-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, nitro, Oalkyl, Oacyl, hydroxyalkyl, aminoalkyl, aminopolyalkyl, alkylamin, guanidino, sucrose, fructose, glucose, galactose, maltose, lactose and mannose, wherein R5, R6, R7, R8 and R9 optionally are individually substituted at least once, wherein the substituents are selected from: O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_ i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, guanidino, sucrose, fructose, glucose, galactose, maltose, lactose or mannose
wherein any of the carbons comprised by Y is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R5, R6, R7 and R8 can be a bond connecting to X, or wherein one or more of the optional substituents R5, R6, R7 and R8 individually or in conjunction are optionally linked to one or more of the optional substituent(s) Ri, R2, R3, R4, R5, R6, R7, R8, R9 and/or to N of formula III and/or to X of formula (II) and or to one of said optional substituents of said Ri, R2, R3, R4, R5, R6, R7, R8, R9 thereby forming one or more rings,
wherein X is a bond linking R2 to R5 to R9 that may be a N linked to R8 to R3 thus forming a ring Q, said Q being a piperazine or piperidine ring, thereby forming the general formula V.
R4 Q R6
R7 (V)
wherein R1, R4, R6 and R7 are optional substituents as defined, wherein the general formula I comprises one ore more amino groups individually selected from primary or secondary or tertiary amines or where the amino group optionally have a further substituent attached thus forming a quaternary ammonium,
with the proviso that if X of formula (II) is phenyl then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or ethylamine or 2-amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or
1 ,2,2,5,5-pentamethylpyrrolidine,
and with the proviso that if X of formula (II) is cyclohexane then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or 2-amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or 1 ,2,2,5,5-pentamethylpyrrolidine
and the proviso that if X of formula (II) is phenyl or cyclohexane Z is not methylamine while Y is ethylamine or an amidino group or 2-amino-1 - hydroxyethyl, and Y is not methylamine while Z is ethylamine or an amidino group,
and the proviso that if X is a bond then Z and Y are not both 4-substituted piperidine,
and the proviso that if X is C1 , then Z and Y are not both 4-aminocyclohexyl, and with the proviso that if Q of formula (V) is N,N'-disubstituted piperazine then the substituting groups are not N-methyl and C2-C4-alkylamine respectively or N,N-dimethyl and C2-C4-alkylamine respectively,
and the proviso that if Q is N-monosubstituted piperazine, then neither Ri nor R4 nor R6 nor R7 is pyridine or C2-3-alkylamine or 4-aminophenyl.
and the proviso that if Q is a piperidine, then R1, R4, R6 and R7 are not selected among N-linked C(2-3)-alkylamine and a para-oriented amino group respectively, nor among N-linked hydrogen and para-oriented C(2-3)-alkylamine respectively,
and the proviso that if X of formula (II) is tetrahydrofurane-3,4-diole then both Z and Y are neither C^alkylamine nor C^alkylguanidine,
and the proviso that if X of formula (II) is 5-amino-6-methoxy-tetrahydro-2H- pyran-3,4-diol then Z is not a C^alkylamine while Y is unsubstituted,
and the proviso that X is not 2,3,4,5-tetrahydroxyhexane while Z and Y are both amine,
and the proviso that if X is a C^alkyl or a N-propyl-N-pentylamine Z and Y are not both amine,
and the proviso that if X is a 1 ,4-butanediamine Z and Y are not both 3-aminopropyl
and the proviso that if X is a C(1_8)alkyl then both Z and Y are not primary amines
or a pharmaceutically acceptable addition salt or hydrate thereof.
for the manufacture of a medicament for the prophylaxis and/or treatment of nephrotoxicity and/or ototoxicity.
Similarly, the invention, in one aspect, relates to a method for the treatment and/or prophylactic treatment of induced cell toxicity, in particular nephrotoxicity and/or ototoxicity, comprising the administration of a compound of formula (I), to a person in need thereof.
When any variable occurs more than once in any constituent, each definition is inde- pendent.
In a further main aspect, the invention relates to a compound having the general formula of wherein
A is independently selected from formula (I) and/or formula (II) and/or formula (III) and/or formula (IV) and/or formula (V) and/or formula (Vl) and/or formula (VII) and/or formula (VIII) as defined above (I) as defined herein, and wherein D is a spacer, q is an integer of 1 -100, p is an integer of 1 -100.
In another aspect of the invention, a combination medicament comprising a compound of the invention or any of the compounds for which a use is described herein and a therapeutic agent for simultaneous, separate or sequential use in cell toxicity therapy, said cell presenting a receptor megalin and/or a receptor cubilin and/or a co-receptor of megalin and cubilin is disclosed.
Detailed description of the invention
The principle of the present invention is to reduce the side effects caused by therapeutic agents, in particular kidney and inner ear damage. The toxicity of the therapeutic agents is due to the accumulation of the therapeutic agent in cells in the organs in question. Thus, the invention focuses on preventing said accumulation in cells. This may for example be performed by inhibiting the binding of the therapeutic agent to the receptor megalin by either blocking a sufficient amount of binding sites on the receptor megalin and/or blocking the therapeutic agent so that it maintains the normal therapeutic effect but is prevented from binding to the receptor.
By the present invention, the novel use of compounds acting as antagonists for use in the manufacture of medicaments for the prophylaxis and/or treatment of induced cell toxicity is disclosed.
Definitions
Alkenyl group: the term "alkenyl" means a non-saturated linear or branched hydrocarbon group including, for example, methylene or ethylene.
Alkyl group: the term "alkyl group" means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like. Preferred alkyls are lower alkyls, i.e. alkyls having 1 to 6 carbon atoms, such as 1 , 2, 3, 4, 5 or 6 carbon atoms.
Alkynyl group: the term "alkynyl" means a non-saturated linear or branched hydrocarbon group including, for example, ethynyl or propynyl.
Aryl represents a hydrocarbon comprising at least one aromatic ring, and may contain from 5 to 18, preferably from 6 to 14, more preferably from 6 to 10, and most preferably 6 carbon atoms. Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenylenyl, and fluorenyl groups. Particularly preferred aryl groups include phenyl, naphthyl and fluorenyl, with phenyl being most preferable. Cell death: in the present context cell death is defined in various ways and covers a cell which has lost all its functions, a cell which has lost a special function, such as hormone synthesis, or a cell which has a reduced capability for further division.
Cell toxicity: an agent is defined as toxic when it is directly capable of causing cell death.
Cycloalkyl means a monovalent saturated carbocyclic compound consisting of one or two rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, aryl- aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylamino- carbonyl, alkylcarbonylamino and arylcarbonylamino.
Form a ring means that the atoms mentioned are connected through a bond when the ring structure is formed. The term "ring" is used synonymously with the term "cyclic".
Heteroalkyl is a saturated linear or branched hydrocarbon group (including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like) wherein one or more carbon atoms are substituted for a heteroatom selected from N, O, S, S(O)0-2, Si or P and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino, or arylcarbonylamino. Heteroalkyls of the present invention may be branched or unbranched and may range from one (1 ) to fifty (50) carbon atoms in length wherin 50% or less, of said carbon atoms may be substituted for N, NH(Q-4), O, S, S(O)0-2, Si, P, Cl, Br.
Heterocvclyl means a monovalent saturated cyclic compound or part of a compound, consisting of one to two rings, of three to eight atoms per ring, incorporating one, two, three or four ring heteroatoms, selected from N, O or S(O)0-2, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, arylaminocarbonyl, alkylcarbonylamino, or arylcarbonylamino. Examples of common heterocyclyls of the present invention include, but is not limited to piperazine and piperidine which may thus be heterocyclyl substituents as defined herin. Such substituents may also be denoted piperazino and piperidino respectively. A further heterocyclyl of the present invention is thiophene.
Heteroaryl means a monovalent aromatic cyclic compound or part of a compound having one to three rings, of four to eight atoms per ring, incorporating one, two, three or four heteroatoms (selected from nitrogen, oxygen, or sulfur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonlamino and arylcarbonylamino.
Induced cell toxicity means a toxic response induced by a therapeutic agent in a cell being exposed to said therapeutic agent.
Monomer: A small entity such as a molecule that may become chemically bonded to other monomers to form an oligomer, polymer or multimer.
Oligomer: A substance consisting of two or more repeating structural units, monomers, connected by chemical bonds.
Polymer: A substance consisting of a very large number of repeating structural units, monomers, connected by chemical bonds.
Polymorph: Variation in chemical and physical properties of a compound such as e.g. crystal lattice, melting point, chemical reactivity, apparent solubility, dissolution rate, optical and electrical properties, vapour pressure, and density. Prophylaxis or prophylactic treatment is not intended to be limited to complete prevention of induced cell toxicity, but also includes incomplete reduction of such toxicity.
Rational number: A number which can be expressed as a ratio of two integers.
Spacer in the present context refers to the atoms directly linking the monomers of formula (I), (II), (III), (IV) or (V). The spacer may also directly link the compounds of formula (I), (II), (III), (IV) or (V) to a therapeutic agent as described by the present combination medicament.
Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.
Therapeutic agent is used synonymously with a medicament, unless otherwise stated.
Novel use of compounds
It is within the scope of the invention that the compounds of the invention may bind to a receptor involved in induced cell toxicity, such as megalin and cubilin, preferably megalin, in order to inhibit binding and optionally uptake of the therapeutic agent into the cell.
The compound is preferably either capable of binding to a sufficient number of binding sites on the receptor(s) and/or of binding to the receptor and sterically hindering the binding of the therapeutic agent or inducing a conformational change of the receptor, thus inhibiting binding of the therapeutic agent.
Structure of the compounds
Regardless of the specific structure of the present compound, the atoms of the compounds must be positioned in a way that allows for the compound to exert its inhibitory effect. Such inhibitory effect may result from the antagonistic binding of the compound to a receptor involved in cell toxicity and/or result from the binding of the compound to a therapeutic agent resulting in the prevention of a binding between the therapeutic agent and a receptor. By binding is meant a binding between the therapeutic agent and a corresponding receptor resulting in a cell toxic response.
Thus, in a main aspect, the present invention relates to the use of a compound comprising a structure of the general formula (I)
[L] m
wherein m is an integer and L is of the general formula (II):
aZj (X)n- bYk
In one aspect of the present invention X is a bond or a C1 -12 alkyl or a C1 -12 heteroalkyl or an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0, one, two, three or four heteroatoms, and n is an integer between 1 and 12,
wherein any component of X may individually be substituted by Z, j times wherein j is an integer from 1 to 12 and wherein Z is a substituent to X of the general formula (III):
R4 N R2
R3
and wherein each substituent Z may exist in a copies wherein a is an integer from 1 to 12, wherein the optional substituents Ri, R2, R3 and R4 individually are selected from a bond to X, or a bond to R1, or a bond to R2, or a bond to R3, or a bond to R4, or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C1-12)-alkyl-aryl, (C1. 12)-alkoxyaryl, heteroaryl-(d-12)-alkyl, heterocyclyl-(C1-12)-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, nitro, Oalkyl, Oacyl, hydroxyalkyl, aminoalkyl, aminopolyalkyl, alkylamin, sucrose, fructose, glucose, galactose, maltose, lactose, mannose or wherein Ri is a hydrogen, R2 is 1 -imino- aminomethyl and R3 , selected from any of the above, connecting the thus formed guanidino group to X, wherein any of the substituents R1, R2, R3 or R4, optionally may be substituted individually at least once, wherein the substituents are selected from: hydrogen, O, OH, phenyl, amine (NH2), imine (NH), aminoalkyl, aminopolyalkyl, alkylamin, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.12)-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1. 12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, nitro, sucrose, fructose, glucose, galactose, maltose, lactose or mannose
wherein any of the carbons comprised by Z is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R1, R2, R3 and R4 can be a bond connecting to X wherein any component of X optionally may be substituted by Y, between k and I times wherein k and I are integers between O and 12 and wherein Y is a substituent described by the general formula (IV):
R6
R5 Rg R7
R8
and wherein each substituent Y may exist in b copies wherein b is an integer from 1 to 12, wherein the optional substituents R5, R6, R7, Rs and R9 individually are selected from a bond to X or a bond to R5, or a bond to R6, or a bond to R7, or a bond to R8, or a bond to R9, or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C1-12)-alkyl-aryl, (d-12)-alkoxyaryl, heteroaryl-(d-12)-alkyl, heterocyclyl-(d- 12)-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, nitro, Oalkyl, Oacyl, hydroxyalkyl, aminoalkyl, aminopolyalkyl, alkylamin, guanidino, sucrose, fructose, glucose, galactose, maltose, lactose and mannose, wherein R5, R6, R7, R8 and R9 optionally are individually substituted at least once, wherein the substituents are selected from: O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-12)-alkyl, heteroaryl-(d-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, guanidino, sucrose, fructose, glucose, galactose, maltose, lactose or mannose
wherein any of the carbons comprised by Y is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R5, R6, R7 and R8 can be a bond connecting to X, or wherein one or more of the optional substituents R5, R6, R7 and R8 individually or in conjunction are optionally linked to one or more of the optional substituent(s) Ri, R2, R3, R4, R5, R6, R7, R8, R9 and/or to N of formula III and/or to X of formula (II) and or to one of said optional substituents of said R1, R2, R3, R4, R5, R6, R7, R8, R9 thereby forming one or more rings,
wherein X is a bond linking R2 to R5 to R9 that may be a N linked to R8 to R3 thus forming a ring Q, said Q being a piperazine or piperidine ring, thereby forming the general formula V.
Ri
R4 Q R6 R7 (V)
wherein R1, R4, R6 and R7 are optional substituents as defined, wherein the general formula I comprises at least two amino groups individually selected from primary or secondary or tertiary amines or where the amino group optionally have a further substituent attached thus forming a quaternary ammonium,
or a pharmaceutically acceptable addition salt or hydrate thereof.
for the manufacture of a medicament for the prophylaxis and/or treatment of induced cell toxicity, in particular nephrotoxicity and/or ototoxicity, i.e. damage of the kidney and/or inner ear. In one embodiment the compound of the present invention wherin X of formula (II) is phenyl or cyclohexane then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or ethylamine or 2- amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or 1 ,2,2,5,5-pentamethylpyrrolidine.
In another embodiment the compound of the present invention wherin X of formula (II) is phenyl or cyclohexane, Z is not methylamine while Y is ethylamine or an amidino group or 2-amino-1 -hydroxyethyl, and Y is not methylamine while Z is ethylamine or an amidino group.
In a further embodiment the compound of the present invention wherin X is a bond, then Z and Y are not both 4-substituted piperidine.
In yet another embodiment the compound of the present invention wherin X is C1 , then Z and Y are not both 4-aminocyclohexyl.
In another embodiment the compound of the present invention wherin Q of formula (V) is N,N'-disubstituted piperazine then the substituting groups are not N-methyl and C2- C4-alkylamine respectively or N,N-dimethyl and C2-C4-alkylamine respectively.
In a further embodiment the compound of the present invention wherin Q is N- monosubstituted piperazine, then neither Ri nor R4 nor R6 nor R7 is pyridine or C2-3- alkylamine or 4-aminophenyl.
In yet another embodiment the compound of the present invention wherin Q is a piperidine, then R1, R4, R6 and R7 are not selected among N-linked C(2-3)-alkylamine and a para-oriented amino group respectively, nor among N-linked hydrogen and para- oriented C(2-3)-alkylamine respectively.
In another embodiment the compound of the present invention wherin X of formula (II) is tetrahydrofurane-3,4-diole then both Z and Y are neither C^alkylamine nor C0. 2>alkylguanidine.
In another embodiment the compound of the present invention wherin X of formula (II) is 5-amino-6-methoxy-tetrahydro-2H-pyran-3,4-diol then Z is not a C(i-2)alkylamine while Y is unsubstituted.
In another embodiment the compound of the present invention X is not 2,3,4,5- tetrahydroxyhexane while Z and Y are both amine,
In another embodiment the compound of the present invention wherin X and the proviso that if X is a C^alkyl or a N-propyl-N-pentylamine Z and Y are not both amine,
In another embodiment the compound of the present invention wherin X is a 1 ,4- butanediamine, Z and Y are not both 3-aminopropyl.
In another embodiment the compound of the present invention wherin X is a C(i_8)alkyl then both Z and Y are not primary amines.
In another embodiment the compound of the present invention is not 3-methylamino-1 - (4-methylpiperazino)-2-propanole, 1 -(3-chlorophenyl)piperazine diHCI (m-CPP), piperazin-2-one-HCI, 2-[4-(2-aminoethyl)piperazin-1 -yl] ethylamine, piperazine anhydrous, 2,4-diamino-6-phenyl-1 ,3,5-triazine, 3,5-diamino-1 ,2,4-triazole, melonamide, arginine-HCI, piperidine, 2,5-piperazinedione, piperazine, piperazin-2- one-HCI, 1 -(2-pyrimidyl)piperazine dihydrochloride, 3-methylamino-1 -(4-methyl- piperazino)-2-propanole, 2-[4-(2-aminoethyl)piperazin-1 -yl]ethylamine, arginine, or 1 - (2-pyrimidyl)-piperazine dihydrochloride.
In one embodiment the compound of the present invention is not and the proviso that the compound is not selected from the group consisting of diaminomethane; 1 ,2- diaminoethane; 1 ,3-diaminopropane; 1 ,4-diaminobutane;
1 ,5-diaminopentane; 1 ,6-diaminohexane; 1 ,7-diaminoheptane; 1 ,8-diaminooctane; 3- methylamino-1 -(4-methylpiperazino)-2-propanole; 4-piperazinoaniline; 1 -(3- chlorophenyl)piperazine ; piperazin-2-one; 2-[4-(2-aminoethyl)piperazin-1 -yl] ethylamine; 2,4-diamino-6-phenyl-1 ,3,5-triazine; 3,5-diamino-1 ,2,4-triazole; malonamide; arginine; piperidine; 2,5-piperazinedione; piperazine; piperazin-2-one- HCI; N-(2-pyrimidyl)-piperazine dihydrochloride; 4,4'-diaminodicyclohexylmethane; trans-1 ,4-diaminocyclohexane; 1 ,3-cyclohexane bis(methylamine); 1 ,4-cyclohexane bis(methylamine); p-Xylylene diamine; m-Xylylene diamine; 1 -(4-pyridyl)-piperazine; 1 ,4-bis(piperidin-1 -ylmethyl)benzene;
2,3,5,6-tetramethyl-1 ,4-xylylenediamine, dihydrochloride; 2,5-dimethyl-1 ,4- xylylenediamine, dihydrochloride; α,α'-(dimethylamino)-p-xylene dihydrobromide; α,α'-(trimethylammonium)-2,5-dimethyl-p-xylene, dihydrochloride; N-(4- Guanidinomethyl-benzyl)-guanidine di-TFA; 3-aminomethyl benzamidine dihydrochloride; 4-aminomethyl benzamidine dihydrochloride; 4-Aminomethyl-2, 3,5,6- tetrachloro-benzylamine dihydrochloride; 4-Aminomethyl-2,3,5,6-tetrafluoro- benzylamine dihydrochloride; 2-(4-Aminomethyl-phenyl)-ethylamine dihydrochloride; 1 ,4-(Diamidino)benzene dihydrochloride; 2-(4-(2-aminoethyl)phenyl) ethanamine dihydrochloride; 3-(4-methylpiperazin-1 -yl) propan-1 -amine; 2-amino-1 -(4- (aminomethyl)phenyl)ethanol dihydrochloride; 1 ,4-di(2-amino-1 -hydroxyethyl)benzene dihydrochloride; 2-(4-methylpiperazin-1 -yl) ethanamine trihydrochloride; 4-(4- methylpiperazin-1 -yl)butan-1 -amine trihydrochloride; 2-(piperazin-1 -yl)ethanamine trihydrochloride; 3-(piperazin-1 -yl)propan-1 -amine trihydrochloride; 3-(4,4- dimethylpiperazin-1 -yl) propan-1 -amine; 1 -(2-aminoethyl)piperidin-4-amine trihydrochloride; 1 -(3-aminopropyl)piperidin-4-amine trihydrochloride; 2-(piperidin-4- yl)ethanamine dihydrochloride; 3-(piperidin-4-yl)propan-1 -amine dihydrochloride; (2R,3S,4S,5R)-2,5-bis(aminomethyl)-tetrahydrofuran-3,4-diol dihydrochloride; (2R,3S,4S,5R)-2,5-bis(guanidinomethyl)-tetrahydrofuran-3,4-diol dihydrochloride; (2R,3S,4S,5R)-2,5-bis(2-aminoethyl)-tetrahydrofuran-3,4-diol dihydrochloride; (2R,3S,4S,5R)-2,5-bis(2-guanidinoethyl)-tetrahydrofuran-3,4-diol dihydrochloride; 4-(piperidin-4-yl)piperidine dihydrochloride; (2R,3S,4S,5R)-2-(2-aminoethyl)-5- (aminomethyl)tetrahydrofuran-3,4-diol; (2R,3S,4R,5R,6S)-5-amino-2-(aminomethyl)-6- methoxytetrahydro-2H-pyran-3,4-diol; (2R,3S,4R,5R,6S)-5-amino-2-(2-aminoethyl)-6- methoxytetrahydro-2H-pyran-3,4-diol;
2,2',2",2'"-(1 ,4-phenylenebis(methylene))bis(azanetriyl)tetraethanol (2R,3R,4R,5R)-1 ,6-diaminohexane-2,3,4,5-tetraol; (2R,3R,4R,5S)-1 ,6-diaminohexane- 2,3,4,5-tetraol dihydrochloride; (2R,3S,4R,5S)-1 ,6-diaminohexane-2,3,4,5-tetraol dihydrochloride; Spermidine or Spermine.
In one embodiment, the compounds of the present invention do not comprise an amide group bound to a carbon. In another embodiment the compound of the present invention is not a derivative of a dimer of an original polyamine comprising an amido group.
When any variable occurs more than once in any constituent, each definition is independent.
When used herein, "separated by X atoms" refers to the shortest path from one atom to another atom in a molecule. For example, "wherein N' and N" are separated by 5 atoms" means that no path from N' to N" passes via fewer than 5 intermediate atoms. In an embodiment of the present invention, a compound is used, wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure, having at least two Z-groups, and/or at least two Y-groups as selected from the general formula (II):
aZj (X)n- bYk
In another important embodiment of the present invention, a compound is used, wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure, having 1 -3 rings, 3-8 ring members and 0 to 4 heteroatoms in each ring such as having 1 -3 rings, 5-6 ring members and 1 or 2 heteroatoms in each ring, for example having 1 -3 rings, 5-6 ring members and no heteroatoms in each ring such as having 1 -2 rings, 3-8 ring members in each and having 0 to 3 heteroatoms, , for example having 1 -3 rings, 5-6 ring members and 3-4 heteroatoms in each ring such as having 1 -2 rings, 3-8 ring members in each and having 3 to 4 heteroatoms, wherein each ring optionally is substituted j times by Z and k times by Y of the general formula (II), such as described in the below table 1 :
Examples of Examples of combinations of combinations of substituents Z and Y substituents Z and Y
Number of Number of Number of Number of
Z Y Z Y
1 0 10 1 1
2 0 10 12
3 0 10 13
4 0 10 14
5 0 10 15
6 0 10 16
7 0 10 17 8 0 10 18
9 0 10 19
10 0 10 20
11 0 11 1
12 0 11 2
13 0 11 3
14 0 11 4
15 0 11 5
16 0 11 6
17 0 11 7
18 0 11
19 0 11 9
20 0 11 10
1 1 11 11
1 2 11 12
1 3 11 13
1 4 11 14
1 5 11 15
1 6 11 16
1 7 11 17
1 8 11 18 OO
1 9 11 19
1 10 11 20
1 11 12 1
1 12 12 2
1 13 12 3
1 14 12 4
1 15 12 5
1 16 12 6
1 17 12 7
1 18 12 8
1 19 12 9
1 20 12 10
2 1 12 11
2 2 12 12
2 3 12 13
2 4 12 14
2 5 12 15
2 6 12 16
2 7 12 17
2 8 12 18
2 9 12 19
2 10 12 20
2 11 13 1
2 12 13 2
2 13 13 3
2 14 13 4
2 15 13 5
2 16 13 6
2 17 13 7
2 18 13 8
2 19 13 9 2 20 13 10
3 1 13 11
3 2 13 12
3 3 13 13
3 4 13 14
3 5 13 15
3 6 13 16
3 7 13 17
3 8 13 18
3 9 13 19
3 10 OO 13 20
3 11 14 1
3 12 14 2
3 13 14 3
3 14 14 4
3 15 14 5
3 16 14 6
3 17 14 7
4 1 14 11
4 2 14 12
4 3 14 13
4 4 14 14
4 5 14 15
4 6 14 16
4 7 14 17
4 8 14 18
4 9 14 19
4 10 14 20
4 11 15 1
4 12 15 2
4 13 15 3
4 14 15 4
4 15 15 5
4 16 15 6
4 17 15 7
4 18 15 8
4 19 15 9
4 20 15 10
5 1 15 11
5 2 15 12
5 3 15 13
5 4 15 14
5 5 15 15
5 6 15 16
5 7 15 17
5 15 18
5 9 15 19
5 10 15 20
5 11 16 1 5 12 16 2
5 13 16 3
5 14 16 4
5 15 16 5
5 16 16 6
5 17 16 7
6 13 17 3
6 14 17 4
6 15 17 5
6 16 17 6
6 17 17 7
6 18 17 8
6 19 17 9
6 20 17 10
7 1 17 11
7 2 17 12
7 3 17 13
7 4 17 14
7 5 17 15
7 6 17 16
7 7 17 17
7 8 17 18
7 9 17 19
7 10 17 20
7 11 18 1
7 12 18 2
7 13 18 3
7 14 18 4
7 15 18 5
7 16 18 6
7 17 18 7
7 18 18 8
7 19 18 9
7 20 18 10
8 1 18 11
8 2 18 12
8 3 18 13 8 4 18 14
8 5 18 15
8 6 18 16
8 7 18 17
8 8 18 18
8 9 18 19
8 10 18 20
8 11 19 1
8 12 19 2
8 13 19 3
8 14 19 4
8 15 19 5
8 16 19 6
8 17 19 7
8 18 19 8
8 19 19 9
8 20 19 10
9 1 19 11
9 2 19 12
9 3 19 13
9 4 19 14
9 5 19 15
9 6 19 16
9 7 19 17
9 8 19 18
9 9 19 19
9 10 19 20
9 11 20 1
9 12 20 2
9 13 20 3
9 14 20 4
9 15 20 5
9 16 20 6
9 17 20 7
9 18 20 8
9 19 20 9
9 20 20 10
10 1 20 11
10 2 20 12
10 3 20 13
10 4 20 14
10 5 20 15
10 6 20 16
10 7 20 17
10 8 20 18
10 9 20 19
10 10 20 20 In one embodiment of the present invention X is selected from the group consisting of cyclopentyl, furan, thiophene, pyrrole, imidazole, oxazole, and pyrrolidene, preferably the group consisting of furan and pyrrole.
In a further embodiment of the present invention X is selected from the group consisting of pyridine, pyrimidine, cyclohexyl, and phenyl, preferably cyclohexyl and phenyl.
In another embodiment of the present invention X is an aromatic, a heteroaromatic or a 5 or 6 membered saturated ring containing 0-2 oxygen atoms, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, nitro, Oalkyl, Oacyl, aminoalkyl, aminopolyalkyl, alkylamin, sucrose, fructose, glucose, galactose, maltose, lactose and mannose.
In yet another important embodiment of the present invention R1, R2, R3, R4 of the Z- group is a C1 -12 alkyl connecting to X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-12)-alkyl, heteroaryl-(d-12)-alkyl, heterocyclyl-(d-12)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose, maltose, lactose and mannose wherein any of the carbons in said C1 -12 alkyl is optionally replaced by oxygen, nitrogen, sulphur, or silicon, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.12)-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1.12)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose,
In another embodiment of the present invention R5, R6, R7, R8 and R9 of the Y-group is a C1 -12 alkyl connecting to X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(d-i2)-alkyl, heterocyclyl-(Ci-i2)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose, maltose, lactose and mannose wherein any of the carbons in said C1 -12 alkyl is optionally replaced by oxygen, nitrogen, sulphur, or silicon, optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose,
In a further embodiment of the present invention X is an aromatic, carbocyclic, a heterocyclic or a heteroaromatic structure having 1 ring with 6 ring members and having O to 1 heteroatoms, said ring optionally being substituted.
In yet another embodiment of the present invention X is a dicyclohexylmethane.
In a further embodiment of the present invention X comprises a heterocyclic ring comprising at least one oxygen atom.
In an important embodiment of the present invention the compound comprises a structure of the formula Vl:
Y Y
wherein Z and Y are substituents as defined herein above. In a further embodiment of the present invention the compound comprises a structure of the formula VII:
wherein Z and Y are substituents as defined herein above.
In yet another embodiment of the present invention the compound comprises a structure of the formula VIII:
wherein Z and Y are substituents as defined.
In an embodiment of the present invention at least one of the Y groups is H and at least one of the Y groups is OH.
In an important embodiment of the present invention at least one of the Z groups comprises a guanidine group.
In another important embodiment of the present invention a Z group comprises a guanidine group.
In a further embodiment of the present invention R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(d-12)- alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In another embodiment of the present invention R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C3-12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_i2)- alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In yet another embodiment of the present invention Ri or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -10 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(Ci2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In a further embodiment of the present invention R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -8 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.12)-alkyl, heteroaryl-(C1.12)- alkyl, heterocyclyl-(C1.12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose. In an embodiment of the present invention Ri or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -6 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(d-12)- alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In yet another embodiment of the present invention R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -4 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In a further embodiment Ri or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or a C1 or a C2 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In an embodiment of the present invention R1 is a C1 or C2 alkyl, substituted at least once with an imine group or substituted at least once with an OH group.
In yet another embodiment of the present invention R1 or R2 or R3 or R4 is C1 .
In a further embodiment of the present invention R1 or R2 or R3 or R4 is a bond. In an embodiment of the present invention R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(d-i2)- alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In another embodiment of the present invention R5 or R6 or R7 or R8 or R9 of the Y- group is a linker to X wherein said linker is a bond, or C3-12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_i2)- alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In yet another embodiment of the present invention R5 or R6 or R7 or R8 or R9 of the Y- group is a linker to X wherein said linker is a bond, or C1 -10 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(Ci-i2)- alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In a further embodiment of the present invention R5 or R6 or R7 or R8 or R9 of the Y- group is a linker to X wherein said linker is a bond, or C1 -8 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_i2)- alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In another aspect of the present invention R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -6 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(d-i2)- alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
it is an embodiment of the present invention R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -4 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_i2)- alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In an embodiment of the present invention R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or a C1 or a C2 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(Ci_i2)- alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In yet another embodiment of the present invention R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl, substituted at least once with an imine group or substituted at least once with an OH group. In further embodiment of the present invention Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are C1 .
In an embodiment of the present invention Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond.
In another embodiment of the present invention R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond or a C1 -12 alkyl linker to X, said linker optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci_i2)-alkyl, heteroaryl-(Ci_i2)- alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In an embodiment of the present invention Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond or C2-8 alkyl linker X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)- alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In another embodiment of the present invention R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C4-6 alkyl linker to X, said alkyl being optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.12)-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1-12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In another embodiment of the present invention Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C1 or a C2 alkyl linker to X, said alkyl being optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
In yet another embodiment of the present invention R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl linker to X, said linker being substituted at least once with an imine group or substituted at least once with an OH group.
In a further embodiment of the present invention Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a linker C1 to X.
In an embodiment of the present invention one or more of R1, R2, R3, R4 , R5, R6, R7, R8 and R9 of the Z-group and/or the Y-group is/are a bond.
In another embodiment of the present invention wherein R1 is a bond and R2 is a C1 -2 alkyl.
In yet another embodiment of the present invention at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 of the Z-group and/or the Y-group is/are a hydrogen.
In a further embodiment of the present invention at least two of R1, R2, R3, R4, R5, R6, R7, R8 and R9 of the Z-group and/or the Y-group are hydrogen. In an embodiment of the present invention three of Ri, R2, R3, R4 of the Z-group and four of R5, R6, R7, Rs and R9 of the Y-group are hydrogen.
In another embodiment of the present invention at least one of R4, R5 and R6 is an hydroxyalkyl, such as hydroxyethyl.
In yet another embodiment of the present invention Ri is linked to R2 or R3 or R4 or R5 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
In an embodiment of the present invention R2 is linked to Ri or R3 or R4 or R5 or R6 or R7 or R8 or R9 forming a ring of 5-6 members.
In another embodiment of the present invention R3 is linked to Ri or R2 or R4 or R5 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
In yet another embodiment of the present invention R4 is linked to Ri or R2 or R3 or R5 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
In a further embodiment of the present invention R5 is linked to Ri or R2 or R3 or R4 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
In an embodiment of the present invention R6 is linked to Ri or R2 or R3 or R4 or R5 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
In another embodiment of the present invention R7 is linked to Ri or R2 or R3 or R4 or R5 or R6 or R8 or R9 thereby forming a ring of 5-6 members.
In yet another embodiment of the present invention R8 is linked to Ri or R2 or R3 or R4 or R5 or R6 or R7 or R9 thereby forming a ring of 5-6 members.
In a further embodiment of the present invention R9 is linked to Ri or R2 or R3 or R4 or R5 or R6 or R7 or R8 thereby forming a ring of 5-6 members. In an embodiment of the present invention one or more of Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R9 is a guanidine group or comprises a guanidine group.
In another embodiment of the present invention two of Ri, R2, R3 and R4 of the Z-group of formula (II) are linked to X, thereby forming one or more rings.
In yet another embodiment of the present invention two of R5, R6, R7, R8 and R9 of the Y-group of formula (II) are linked to X, thereby forming one or more rings.
In a further embodiment of the present invention at least one of said rings has 5 members.
In an embodiment of the present invention one of either R1 or R2 or R3 or R4 of the Z- group of formula (II) is linked to X and to a non-self member among R1, R2, R3 and R4, thereby generating a ring of 6 members, further comprising an atomic bridge.
In another embodiment of the present invention one of R1, R2, R3 and R4 of the Z-group of formula (II) is linked to X and to one of either R5 or R6 or R7 or R8 or R9 of the Y- group of formula II, thereby generating a ring of 6 members, further comprising an atomic bridge.
In yet another embodiment of the present invention, R1 and/or R4 and/or R6 and/or R7 of the general formula (V) is/are unsubstituted C1 -C12 alkyl(s).
In a further embodiment of the present invention R1 and/or R4 and/or R6 and/or R7 of the general formula (V) is/are substituted C1 -C12 alkyl(s).
In an embodiment of the present invention R1 and/or R4 and/or R6 and/or R7 of the general formula (V) is/are alkylbenzene.
In another embodiment of the present invention R1 and/or R4 and/or R6 and/or R7 of the general formula (V) is/are alkylamine(s) and in yet another embodiment of the present invention said alkylamine(s) is/are unsubstituted. In yet another embodiment of the present invention Ri and/or R4 and/or R6 and/or R7 of the general formula (V) is/are alkylamine(s) individually optionally substituted once or twice or more wherein the substituents are selected from hydrogen, O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, alkylpolyamine, nitro, sucrose, fructose, glucose, galactose or maltose.
In a further embodiment of the present invention R1 and/or R4 and/or R6 and/or R7 of the general formula (V) is/are H.
In an embodiment of the present invention R1, R4, R6 or R7 of the general formula (V) individually or in conjunction form(s) a piperazine or piperidine ring.
In another embodiment of the present invention one or more of any of R1, R4, R6 or R7 of the general formula (V) is H or CH3.
In yet another embodiment of the present invention R1, R4, R6 or R7 of the general formula (V) is a primary, secondary, tertiary or quaternary amine or a secondary, tertiary or quaternary d-^-alkylamine.
In a further embodiment of the present invention X is a bond connecting R2 and R5 of the general formulas (N-IV).
In an embodiment of the present invention X is a bond connecting R2 of the Z-group of formula (II) and R5 of the Y-group of formula I and none of R1, R3, R4, and R6 R7, R8 is linked to another substituent R1-R8.
In another embodiment of the present invention R2 of the general formula (III) is a bond linked to X of the general formula (II) and R5 of the general formula (III) is C1 -12 alkyl substituted at least once with an OH group.
In yet another embodiment of the present invention R2 of the general formula (III) is C4 alkyl substituted two, three or four times with an OH group. In a further embodiment of the present invention one, two or three or all of R3, R4, R5, and R6 of the general formulas (III-IV) are hydrogen.
In an embodiment of the present invention the compound of the general formula (I) has a polybasic charge distribution.
In an important embodiment of the present invention the compound of the general formula (I) has at least two positively charged nitrogens under physiological conditions wherein said positively charged nitrogens are separated by 2-1 OO atoms, such as 2-3 atoms, e.g. 3-4 atoms, such as 3-4 atoms e.g. 4-5 atoms, such as 5-6 atoms e.g. 6-7 atoms, such as 7-8 atoms, e.g.8-9 atoms, suchas 9-10 atoms, e.g. 10-1 1 atoms, such as 1 1 -12 atoms, e.g. 12-13 atoms, such as 13-14 atoms, e.g. 14-15 atoms, such as 15- 16 atoms, e.g. 16-17 atoms, such as 17-18 atoms, e.g. 18-19 atoms, such as 19-20 atoms, e.g. 20-25 atoms, such as 25-30 atoms, e.g. 30-35 atoms, such as 35-40 atoms, e.g. 40-45 atoms, such as 45-50 atoms, e.g. 50-55 atoms, such as 55-60 atoms, e.g. 60-65 atoms, such as 65-70 atoms, e.g. 70-75 atoms, such as 75-80 atoms, e.g. 80-85 atoms, such as 85-90 atoms, e.g. 90-95 atoms, such as separated by 95-100 atoms.
In an embodiment of the present invention the compound of the general formula (I) does not comprise a substituted or unsubstituted piperazine or piperidine structure.
In another embodiment of the present invention the compound does not comprise a ring structure having 3 nitrogen atoms.
In yet another embodiment of the present invention the compound of the general formula (I) is capable of binding to the receptor megalin and/or the receptor cubilin.
In a preferred embodiment, the compound or combination of compounds of the present invention is/are selected from the group consisting of 2,4 Diamino-6-hydroxypyrimidine; 2-Phthalimido acetamide; 1 -(3-chlorophenyl)piperazine; 1 -(3-chlorophenyl)piperazine hydrochloride; 3,6-diaminoacridin sulphate (proflavin); 3,7-diaminoanthraquinone; 1 ,4-diaminobenzene; 4,4'diaminobiphenyl; 1 ,8-diamino-4,5-dihydroxyanthraquinone; 2,5-diamino2,5-dimethylhexane; 3,3'diaminodipropylamine; 3,3'diaminodipropylamine;
2,7-diaminofluorene; 1 ,8-diamino-p-menthane; 3,7-diamino-2-methoxyfluorene;
1 ,8-diaminonaphtalene; 1 ,5-diaminonaphtalene; 2,7-diaminonaphtalene;
DL α,α-diaminopimelic acid; Tetramethyl-1 ,6-hexanediamine; 1 ,6-diaminohexane- N,N,N',N'-tetraacetate; N-(2-Pyrimidinyl)-piperazine dihydrochloride; 3-methyl-2- piperazinone; 2,2'-(2-(benzo[d][1 ,3]dioxol-5-yl)piperazine-1 ,4-diyl)diethanamine;
Adipic acid dihydrazide; 1 ,1 -Hexamethylenebis(5-(4-chlorophenyl)biguanide) hexa hydrochloride (Chlorhexidine); 2,2'-(2-(3,4,5-trimethoxyphenyl)piperazine-1 ,4- diyl)diethanamine; L-Lysine hydroxamate hydrochloride; Bis-(6-aminohexyl)-amine; 4-(aminomethyl)benzamide; 2,2'-(1 ,4-diazepane-1 ,4-diyl)diethanamine tetrahydrochloride; 2,2'-(2-phenylpiperazine-1 ,4-diyl)diethanamine tetrahydrochloride;
Diethylenetriamine; (2R,3s,4S)-1 ,5-diaminopentane-2,3,4-triol dihydrochloride;
Suberohydroxamic acid; L-Arginine hydroxamate hydrochloride; (2R,3r,4S)-1 ,5- diaminopentane-2,3,4-triol dihydrochloride; N,N'-dihydroxy-1 ,4-Benzenedicarboxamide; 3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)dipropanoic acid;
3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)dipropan-1 -ol dihydrochloride;
(2'R)-2,2'-(1 ,4-phenylenebis(methylene))bis(azanediyl)dibutan-1 -ol dihydrochloride;
4,4'-(1 ,4-phenylenebis(methylene))bis(azanediyl)dibutan-1 -ol dihydrochloride;
Trans 2,2'-(cyclohexane-1 ,4-diyl)diethanamine dihydrochloride; N1 ,N6-dihydroxyadipamide; Polypropylenimine-tetraamine Dendrimer;
2, 2'-(2-(4-fluorophenyl)piperazine-1 ,4-diyl)diethanamine tetrahydrochloride;
N1 ,N1 '-(ethane- 1 ,2-diyl)dipropane-1 ,3-diamine; N1 ,N1 '-(ethane- 1 ,2-diyl)diethane-1 ,2- diamine; 2-(3-(naphthalen-1 -yl)piperazin-1 -yl)ethanamine trihydrochloride;
6,6'-(piperazine-1 ,4-diyl)dihexan-1 -amine; 1 ,4,8,1 1 -tetraazacyclotetradecane; N1 ,N1 '-(propane- 1 ,3-diyl)diethane-1 ,2-diamine;
N,N'-Bis-(2-aminoethyl)-butane-1 ,4-diamine tetrahydrochloride;
6,6'-(2-phenylpiperazine-1 ,4-diyl)dihexan-1 -amine tetrahydrochloride;
3,3'-(2-phenylpiperazine-1 ,4-diyl)dipropan-1 -amine tetrahydrochloride;
3,3'-(piperazine-1 ,4-diyl)dipropan-1 -amine tetrahydrochloride; 1 -(4-aminobutyl)guanidine sulfate; 4,4'-(piperazine-1 ,4-diyl)dibutan-1 -amine tetra hydrochloride; (1 ,2,3,4-tetrahydroisoquinolin-6-yl)methanamine dihydrochloride;
5,5'-(piperazine-1 ,4-diyl)dipentan-1 -amine tetra hydrochloride;
1 ,4-phenylenedimethanol; Mannitol; 2,2'-(piperazine-1 ,4-diyl)diethanol;
4-(aminomethyl)aniline; 4-(2-aminoethyl)aniline; N1 -(6-aminohexyl)-N1 -(4- (aminomethyl)benzyl)hexane-1 ,6-diamine tetra hydrochloride; (3-(piperazin-1 -ylmethyl)phenyl)methanamine trihydrochloride;
Deoxystreptamine dibromide; 4-Aminomethylbenzene sulfonamide;
1 -(4-hydoxyphenyl)piperazine; 1 -(4-methylphenyl)piperazine;
N-phenylpiperazine; 1 -(3-methoxyphenyl)piperazine; 4-piperazinobenzonitrile; 1 -(2-cyanophenyl)piperazine; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(6- aminohexyl)hexane-1 ,6-diamine); 2,4,6-tris((dimethylamino)methyl)phenol;
2-(3,4-dihydroquinoxalin-1 (2H)-yl)ethanamine trihydrochloride;
4,4'-ethylenedipiperidine dihydrochloride; 2-amino-6-methyl-4(3h)-quinazolone;
3,4-dihydroxybenzylamine hydrobromide; Tyramine hydrochloride; 2-(1 -piperazino)phenol; 1 -piperonylpiperazine; 4-(2-aminoethyl)benzene-sulfonamide;
2-benzyl-2-imidazoline hydrochloride; 1 -(3,4-dichlorophenyl)-piperazine hydrochloride;
1 -(4-nitrophenyl)piperazine; N-benzylethylenediamine; 4-amino-1 -benzylpiperidine;
4-nitrobenzylamine; N1 ,N1 -dimethyl-1 -phenylethane-1 ,2-diamine;
Dopamine hydrochloride; 1 -phenylethylpiperazine; 1 -(4-methoxyphenyl)-Piperazine dihydrochloride; N-(2-hydroxyethyl)piperazine; 3-amino-4-hydroxybenzhydrazide;
1 -(2-aminoethyl)-4-benzylpiperazine; trans-1 -Cinnamylpiperazine;
2-[4-(3-chlorophenyl)piperazin-1 -yl]-N-hydroxyethanimidamide;
N-hydroxy-2-[4-(2-methoxyphenyl)piperazin-1 -yl]ethanimidamide;
(4-(piperazin-1 -ylmethyl)phenyl)methanamine trihydrochloride; (1 S,2S)-(+)-2-amino-1 -phenyl-1 ,3-propanediol;
1 -(2-(N,N-Bis-(2-hydroxypropyl)-amino)-ethyl)-4-(2-hydroxypropyl)-piperazine;
N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(4-aminobutyl)butane-1 ,4-diamine) hexahydrochloride; Aminoguanidine hydrogencarbonate; Aminoguanidine hemisulfate
(1/2); Aminoguanidine nitrate; Aminoguanidine hydrochloride; Tegaserod Maleate; Alanine anhydride; 1 ,1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 -diyl))diguanidine tetrahydrochloride; Neamine tetrahydrochloride; Arcaine sulfate; 1 ,4-bis(piperazin-1 - ylmethyl)benzene tetrahydrochloride; 1 -(2-chlorophenyl)biguanide hydrochloride;
1 -(4-chlorophenyl)biguanide hydrochloride; 1 -(4-fluorophenyl)biguanide hydrochoride;
1 -(3-chlorophenyl)biguanide hydrochloride; 2,2'-(2-methylpiperidine-1 ,4- diyl)diethanamine tetra hydrochloride; 1 ,1 -Dimethylbiguanid hydrochloride;
N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 -diyl))bis(N1 -(2-aminoethyl)ethane-1 ,2- diamine) octa hydrochloride; 2,2'-(4,4'-(1 ,4-phenylenebis(methylene))bis(piperazine-
4,1 -diyl))diethanamine hexahydrochloride;
N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(2-aminoethyl)ethane-1 ,2-diamine) hexa hydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(3-aminopropyl)propane- 1 ,3-diamine) hexa hydrochloride; N1 ,N1 '-(butane-1 ,4-diyl)bis(N3-benzyl-N1 -(3-
(benzylamino)propyl)propane-1 ,3-diamine) hexahydrochloride; Tris-(2-aminoethyl)- amine; Tetraethylenepentamine; Pentaethylenehexamine; 3-amino-6aminomethyl- tetrahydro-pyran-2,4,5-triol dihydrochloride; Hexamethionium hydroxide; Tris(3-aminopropyl)amine; 2-((4-(2-hydroxyethyl)piperazin-1 -yl)methyl)piperidin-3-ol;
N1 ,N1 '-(1 ,4-phenylenebis(methylene))dibutane-1 ,4-diamine tetrahydrochloride;
N1 ,N6-dimethyl-N1 -(6-(methylamino)hexyl)hexane-1 ,6-diamine;
N1 ,N1 -bis(6-aminohexyl)terephthalamide; N,N-bis(6-aminohexyl)benzamide;
N1 -(6-aminohexyl)-N1 -benzylhexane-1 ,6-diamine tri hydrochloride; 2,2'-(1 ,4-phenylene)bis(1 -(piperazin-1 -yl)ethanone) di hydrochloride;
1 ,4-bis(2-(piperazin-1 -yl)ethyl)benzene tetra hydrochloride;
N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N6-methyl-N1 -(6-
(methylamino)hexyl)hexane-1 ,6-diamine); N1 ,N1 '-(1 ,4- phenylenebis(methylene))dipropane-1 ,3-diamine tetrahydrochloride; DL-α-Difluoromethylornithine hydrochloride;
N1 -(2-aminoethyl)-N1 -benzylethane-1 ,2-diamine trihydrochloride;
N1 ,N4-bis(3-(piperazin-1 -yl)propyl)terephthalamide tetrahydrochloride;
N2,N2,N5,N5-tetrakis(6-aminohexyl)pyridine-2,5-dicarboxamide pentahydrochloride;
6,6'-(1 ,4-phenylenebis(methylene))bis((6-aminohexyl)azanediyl)Dihexanamide tetrahydrochloride; N1 ,N1 ,N4,N4-tetrakis(3-aminopropyl)succinamide tetrahydrochloride; 3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)bis(1 - aminopropan-2-ol) tetrahydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))diethane-
1 ,2-diamine tetrahydrochloride; 4-(3-aminopropyl)morpholine; 1 -(3-aminopropyl)- imidazol; 1 -(2-(dimethylamino)ethyl)piperazine; 2-(aminomethyl)-2-methyl-1 ,3- propanediamine; 4-(1 -pyrrolidinyl)-piperidine; N1 ,N1 '-(2,2'-(piperazine-1 ,4- diyl)bis(ethane-2,1 -diyl))dipropane-1 ,3-diamine; N1 -(2-aminoethyl)-N1 -(2-(4-(2- aminoethyl)piperazin-1 -yl)ethyl)ethane-1 ,2-diamine hexa hydrochloride;
N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 -diyl))diethane-1 ,2-diamine hexa hydrochloride; 3,3',3",3'"-(1 ,4-phenylenebis(methylene))bis(azanetriyl)tetrakis(1 - aminopropan-2-ol) hexa hydrochloride; N1 ,N1 '-(pyridine-2,6- diylbis(methylene))dipropane-1 ,3-diamine pentahydrochloride;
2, 2'-(1 ,4-phenylenebis(methylene))bis(oxy)dipropane-1 ,3-diamine;
2,2'-(1 ,4-phenylenebis(methylene))bis(oxy)dipropane-1 ,3-diamine tetra hydrochloride;
N1 -(3-aminopropyl)-N1 -(2-(piperazin-1 -yl)ethyl)propane-1 ,3-diamine pentahydrochloride; N1 ,N1 '-(thiophene-2,5-diylbis(methylene))dipropane-1 ,3-diamine tetrahydrochloride; N1 ,N1 '-(pyridine-2,5-diylbis(methylene))bis(N1 -(6- aminohexyl)hexane-1 ,6-diamine) hepta hydrochloride; 2,2'-(4,4'-(propane-1 ,3- diyl)bis(piperazine-4,1 -diyl))diethanamine hexa hydrochloride;
N1 -(2-aminoethyl)propane-1 ,3-diamine; 2-(phenylthio)ethanamine hydrochloride; N1 -phenylethane-1 ,2-diamine; (R)-2-amino-3-(benzylthio)propanoic acid;
(R)-2-amino-3-(benzylthio)propan-1 -ol; (R)-2-amino-3-(p-tolylthio)propanoic acid;
N1 ,N6-dipropylhexane-1 ,6-diamine; 2-(4-nitrophenyl)ethanamine hydrochloride;
2-phenoxyethanamine; 3-phenylpropan-1 -amine; 2-(4-nitrophenoxy)ethanamine hydrochloride; 2-(benzylthio)ethanamine hydrochloride; 2-phenylethanamine hydrochloride; (S)-2,6-diamino-N-(4-nitrophenyl)hexanamide di hydrobromide; methyl 2-acetamidoacetate (S)-2,6-diaminohexanoate acetate;
2-amino-N-(4-nitrophenyl)acetamide; (S)-6-amino-2-((S)-2,6- diaminohexanamido)hexanoic acid di hydrochloride;
2,2'-(1 ,4-phenylenebis(sulfanediyl))diethanamine di hydrochloride; N1 ,N1 '-(3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)bis(propane-3,1 - diyl))dibutane-1 ,4-diamine hexa hydrochloride; N1 ,N1 '-(pyridine-3,5- diylbis(methylene))dipropane-1 ,3-diamine penta-hydrochloride;
2,2'-(4,4'-(pentane-1 ,5-diyl)bis(piperazine-4,1 -diyl))diethanamine hexa hydrochloride;
N1 ,N1 '-(3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)bis(propane-3,1 -diyl))bis(N4- (3-aminopropyl)butane-1 ,4-diamine) octa hydrochloride;
3-(phenylthio)butan-1 -amine hydrochloride; 2-(phenylsulfinyl)ethanamine hydrochloride; 2-(phenylsulfonyl)ethanamine hydrochloride or para sulfinylethanamine phenylsulfinyl-ethanamine di hydrochloride;
In a more preferred embodiment the compounds of the present invention are selected from the group consisting of Bis-(6-aminohexyl)-amine; 2,2'-(2-phenylpiperazine-1 ,4- diyl)diethan amine tetrahydrochloride;
3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)dipropan-1 -ol dihydrochloride;
N1 ,N1 '-(ethane- 1 ,2-diyl)dipropane-1 ,3-diamine; 2-(3-(naphthalen-1 -yl)piperazin-1 - yl)ethanamine trihydrochloride; 6,6'-(piperazine-1 ,4-diyl)dihexan-1 -amine;
N1 ,N1 '-(propane- 1 ,3-diyl)diethane-1 ,2-diamine; 6,6'-(2-phenylpiperazine-1 ,4- diyl)dihexan-1 -amine tetrahydrochloride; N1 -(6-aminohexyl)-N1 -(4-
(aminomethyl)benzyl)hexane-1 ,6-diamine tetra hydrochloride;
N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(6-aminohexyl)hexane-1 ,6-diamine); 1 -(2-aminoethyl)-4-benzylpiperazine; Neamine tetrahydrochloride; Arcaine sulfate; N1 ,N1 '-(butane- 1 ,4-diyl)bis(N3-benzyl-N1 -(3-(benzylamino)propyl)propane-1 ,3- diamine) hexahydrochloride; Pentaethylenehexamine; N1 -(6-aminohexyl)-N1 - benzylhexane-1 ,6-diamine tri hydrochloride; N1 ,N1 '-(1 ,4- phenylenebis(methylene))bis(N6-methyl-N1 -(6-(methylamino)hexyl)hexane-1 ,6- diamine); N1 ,N1 '-(1 ,4-phenylenebis(methylene))diethane-1 ,2-diamine tetrahydrochloride; N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 -diyl))diethane-1 ,2- diamine hexa hydrochloride, N1 ,N1 '-(pyridine-2,5-diylbis(methylene))bis(N1 -(6- aminohexyl)hexane-1 ,6-diamine) hepta hydrochloride; 2,2'-(4,4'-(propane-1 ,3- diyl)bis(piperazine-4,1 -diyl))diethanamine hexa hydrochloride; N1 ,N1 '-(3,3'-(1 ,4- phenylenebis(methylene))bis(azanediyl)bis(propane-3,1 -diyl))dibutane-1 ,4-diamine hexa hydrochloride; 2,2'-(4,4'-(pentane-1 ,5-diyl)bis(piperazine-4,1 -diyl))diethanamine hexa hydrochloride; N1 ,N1 '-(pyridine-3,5-diylbis(methylene))dipropane-1 ,3-diamine penta -hydrochloride; N1 ,N1 '-(3,3'-(1 ,4- phenylenebis(methylene))bis(azanediyl)bis(propane-3,1 -diyl))bis(N4-(3- aminopropyl)butane-1 ,4-diamine) octa hydrochloride.
In an even more preferred embodiment the compounds of the present invention are selected from the group consisting of Trans 2,2'-(cyclohexane-1 ,4-diyl)diethanamine dihydrochloride; Polypropylenimine-tetraamine Dendrimer; Tris-(2-aminoethyl)-amine; N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 - diyl))dipropane-1 ,3-diamine; N1 ,N1 '-(pyridine-2,6-diylbis(methylene))dipropane-1 ,3- diamine pentahydrochloride and 2,2'-(1 ,4-phenylenebis(sulfanediyl))diethanamine di hydrochloride.
In the most preferred embodiment the compounds of the present invention are selected from the group consisting of 3,3'-(piperazine-1 ,4-diyl)dipropan-1 -amine tetrahydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(4-aminobutyl)butane- 1 ,4-diamine) hexahydrochloride; N1 ,N1 '-(2,2'-(piperazine-1 ,4-diyl)bis(ethane-2,1 - diyl))bis(N1 -(2-aminoethyl)ethane-1 ,2-diamine) octa hydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(2-aminoethyl)ethane-1 ,2-diamine) hexa hydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))bis(N1 -(3-aminopropyl)propane- 1 ,3-diamine) hexa hydrochloride; N1 ,N1 '-(1 ,4-phenylenebis(methylene))dipropane-1 ,3- diamine tetrahydrochloride; 3,3'-(1 ,4-phenylenebis(methylene))bis(azanediyl)bis(1 - aminopropan-2-ol) tetrahydrochloride; N1 -(2-aminoethyl)-N1 -(2-(4-(2- aminoethyl)piperazin-1 -yl)ethyl)ethane-1 ,2-diamine hexa hydrochloride; 3,3',3",3'"-(1 ,4-phenylenebis(methylene))bis(azanetriyl)tetrakis(1 -aminopropan-2-ol) hexa hydrochloride; 2,2'-(1 ,4-phenylenebis(methylene))bis(oxy)dipropane-1 ,3-diamine and 2,2'-(1 ,4-phenylenebis(methylene))bis(oxy)dipropane-1 ,3-diamine tetra hydrochloride
The present inventors have found a correlation between the structural arrangement of the compounds of the present invention and their efficacy as inhibitors of aminoglycoside uptake in the kidneys through the receptors megalin and cubilin. The inventors have also discovered that the toxic effect may be avoided through optimizing the orientation and distance between amino groups and other electron rich elements of the compounds of the present invention.
Accordingly, in one embodiment the compounds of the present invention are selected from the group consisting of a) Compounds that contain at least one, preferably at least two, non-cyclic alkyl- amine group(s), wherein said alkyl amine groups may be substituted as described herein (above). b) Alkyl-amine deficient group(s) that are not part of ring structures.
Examples of a) include but are not limited to RC029, RC030, RC032, RC037, RC038, RC040, RC088, RC091 , RC092, RC093, RC094, R095, RC096,
RC097, RC100, RC103, RC105, RC106, RC107, RC108, RC109, RC1 12,
RC1 13, RC1 14, RC1 15, RC1 16, RC1 17, RC1 18, RC1 19, RC120, RC121 ,
RC122, RC123, RC124, RC125, RC126, RC127, RC131 , RC132, RC134,
RC135, RC137, RC144, RC145, RC146, RC149, RC150, RC153, RC157, RC159, RC160, RC161 , RC166, RC171 , RC172, RC173, RC174, RC177,
RC179, RC186, RC188, RC189, RC190, RC191 , RC192, RC193, RC194,
RC195, RC196, RC197, RC198, RC200, RC201 , RC202, RC203, RC204,
RC207, RC208, RC209, RC210, RC212, RC213, RC214, RC215, RC216,
RC217, RC218, RC219, RC220, RC222, RC223, RC224, RC225, RC226, RC227, RC227-1 , RC228, RC229, RC230, RC231 , RC233, RC234, RC235,
RC236, RC237, RC238, RC239, RC240, RC241 , RC242, RC243, RC244,
RC245, RC246, RC247, RC248, RC249, RC250, RC251 , RC252, RC253,
RC254, RC255, RC256, RC257, RC258 (of figure 1 ), and analogues thereof. Examples of b) include but is not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC057, RC089, RC090, RC101 , RC102, RC104, RC1 10, RC128, RC129, RC130, RC136, RC138, RC139, RC140, RC141 , RC142, RC143, RC147, RC148, RC151 , RC152, RC154, RC155, RC156, RC158, RC162,
RC163, RC164, RC165, RC168, RC169, RC170, RC175, RC176, RC178, RC180, RC181 , RC182, RC183, RC184, RC185, RC187, RC199, RC205, RC206, RC21 1 , RC221 (of figure 1 ), and analogues thereof.
In another embodiment, and for the reasons mentioned above comprising optimizing the inhibitory effect and avoiding toxic side-effects, the compounds of the present invention are selected from the group consisting of a) Compounds that contain one or more guanidine groups or at least one, preferably at least two, alkyl-amine group(s), that are not part of a ring structure wherein said alkyl amine groups may be substituted as described herein above.
b) Compounds which are deficient of non-cyclic alkyl-amine group(s) and guanidines.
Examples of a) include but are not limited to RC029, RC030, RC032, RC037,
RC038, RC088, RC091 , RC092, RC093, RC094, R095, RC096, RC097, RC100, RC102, RC103, RC105, RC106, RC107, RC108, RC109, RC1 12, RC1 13, RC1 14, RC1 15, RC1 16, RC1 17, RC1 18, RC1 19, RC120, RC121 , RC122, RC123, RC124, RC125, RC126, RC127, RC131 , RC132, RC134, RC135, RC137, RC144, RC145, RC146, RC149, RC150, RC153, RC157,
RC159, RC160, RC161 , RC166, RC171 , RC172, RC173, RC174, RC175, RC177, RC178, RC179, RC180, RC186, RC188, RC189, RC190, RC191 , RC192, RC193, RC194, RC195, RC196, RC197, RC198, RC200, RC201 , RC202, RC203, RC204, RC207, RC208, RC209, RC210, RC212, RC213, RC214, RC215, RC216, RC217, RC218, RC219, RC220, RC222, RC223,
RC224, RC225, RC226, RC227, RC227-1 , RC228, RC229, RC230, RC231 , RC233, RC234, RC235, RC236, RC237, RC238, RC239, RC240, RC241 , RC242, RC243, RC244, RC245, RC246, RC247, RC248, RC249, RC250, RC251 , RC252, RC253, RC254, RC255, RC256, RC257, RC258 (of figure 1 ), and analogues thereof. Examples of b) include but is not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC057, RC089, RC090, RC101 , RC104, RC1 10, RC128, RC129, RC130, RC136, RC138, RC139, RC140, RC141 , RC142, RC143, RC147,
RC148, RC151 , RC152, RC154, RC155, RC156, RC158, RC162, RC163, RC164, RC165, RC168, RC169, RC170, RC176, RC181 , RC182, RC183, RC184, RC185, RC187, RC199, RC205, RC206, RC21 1 , RC221 (of figure 1 ), and analogues thereof.
The efficacy of the compounds of the present invention to act as inhibitors of aminoglycoside uptake, is dependant on the number of, and distance between the non- cyclic alkyl-amine groups comprised by the general formula (II). Accordingly, in one embodiment, the compounds of the present invention are selected from the group consisting of
a) compounds lacking amines in non-cyclic alkyl chains, b) compounds comprising one amine in non-cyclic alkyl chains, c) compounds comprising two amines in non-cyclic alkyl chains, and d) compounds comprising three or more amines in non-cyclic alkyl chains.
Examples of a) include but are not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC057, RC089, RC090, RC101 , RC102, RC104, RC1 10, RC1 16, RC128, RC129, RC130, RC136, RC138, RC139, RC140, RC141 , RC142,
RC143, RC147, RC148, RC151 , RC152, RC154, RC155, RC156, RC158, RC162, RC163, RC164, RC165, RC168, RC169, RC170, RC175, RC176, RC178, RC180, RC181 , RC182, RC183, RC184, RC185, RC187, RC199, RC205, RC206, RC21 1 , RC221 (of figure 1 ), and analogues thereof.
Examples of b) include but are not limited to RC032, RC094, RC1 16, RC126, RC131 , RC132, RC135, RC137, RC146, RC149, RC150, RC153, RC159, RC161 , RC166, RC171 , RC172, RC173, RC179, RC196, RC217, RC218, RC219, RC234, RC236, RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC247, RC248, RC255, RC256, RC257 (of figure 1 ) and analogues thereof.
Examples of c) include but are not limited to RC029, RC037, RC038, RC040, RC088, RC091 , RC092, RC095, RC096, RC100, RC103, RC105, RC106,
RC107, RC108, RC109, RC1 13, RC1 17, RC121 , RC122, RC123, RC125, RC127, RC157, RC160, RC177, RC186, RC189, RC197, RC209, RC231 , RC235, RC239, RC246, RC250, RC253, RC258 (of figure 1 ) and analogues thereof.
Examples of d) include but are not limited to RC030, RC093, RC097, RC1 12, RC1 14, RC1 15, RC1 18, RC1 19, RC120, RC124, RC134, RC144, RC145, RC174, RC188, RC190, RC191 , RC192, RC193, RC194, RC195, RC198, RC200, RC201 , RC202, RC203, RC204, RC207, RC208, RC210, RC212, RC213, RC214, RC215, RC216, RC220, RC222, RC223, RC224, RC225,
RC226, RC227, RC227-1 , RC228, RC229, RC230, RC233, RC249, RC251 , RC252, RC254 (of figure 1 ) and analogues thereof.
In another embodiment, wherin the inhibitory effect may be optimized while avoiding toxic side-effects, the compounds of the present invention comprise three or more non- cyclic amines in unbranched non-cyclic alkyl chains. Examples thereof include but are not limited to RC030, RC093, RC097, RC1 14, RC1 15, RC1 18, RC1 19, RC120, RC124, RC194, RC195, RC200, RC208, RC215, RC216, RC222, RC224, RC226, RC229, RC233, RC251 , RC252, RC254 (of figure 1 ) and analogues thereof.
In another embodiment, wherin the inhibitory effect may be optimized while avoiding toxic side-effects, the compounds of the present invention comprise three or more non- cyclic amines in branched alkyl chains. Examples thereof include but are not limited to RC1 12, , RC134, RC144, RC145, RC174, RC188, RC190, RC191 , RC192, RC193, RC198, RC201 , RC202, RC203, RC204, RC207, RC210, RC212, RC213, RC214,
RC220, RC223, RC225, RC227, RC227-1 , RC228, RC230, RC249 (of figure 1 ) and analogues thereof. The efficacy of the compounds of the present invention are dependent on the nature of the spacer region X of the general formula (II). Accordingly, in one embodiment, the compounds of the present invention are selected from the group consisting of: a) cyclic structures, and b) non-cyclic structures.
Examples of a) include but are not limited to RC001 , RC006, RC014, RC014-1 RC023, RC024, RC025, RC026, RC028, RC031 , RC032, RC033, RC034, RC035, RC036, RC056, RC057, RC088, RC090, RC091 , RC094, RC095, RC096, RC104, RC105, RC106, RC107,
RC108, RC109, RC1 13, RC1 16, RC1 17, RC1 18, RC121 , RC122, RC123, RC125, RC126, RC127, RC128, RC130, RC131 , RC132, RC134, RC135, RC136, RC137, RC138, RC139, RC140, RC141 , RC142, RC143, RC144, RC145, RC146, RC147, RC148, RC149, RC150, RC151 , RC152, RC153, RC154, RC155, RC156, RC157,
RC158, RC159, RC160, RC161 , RC162, RC163, RC164, RC165, RC166, RC168, RC169, RC170, RC171 , RC172, RC173, RC174, RC176, RC178, RC179, RC181 , RC182, RC183, RC184, RC185, RC186, RC188, RC189, RC190, RC191 , RC192, RC196, RC199, RC200, RC202, RC203, RC204, RC205, RC206, RC207, RC208,
RC210, RC21 1 , RC212, RC213, RC215, RC216, RC217, RC218, RC219, RC221 , RC222, RC223, RC224, RC225, RC226, RC227, RC227-1 , RC228, RC229, RC230, RC231 , RC234, RC235, RC236, RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC246, RC248, RC250, RC251 , RC252, RC253, RC254, RC255,
RC256, RC257, RC258 (of figure 1 ), and analogues thereof.
Examples of b) include but are not limited to RC029, RC030, RC037, RC038, RC040, RC089, RC090, RC091 , RC092, RC093, RC097,
RC100, RC101 , RC102, RC103, RC1 14, RC1 15, RC1 19, RC120, RC124, RC129, RC175, RC177, RC180, RC187, RC193, RC194, RC195, RC197, RC198, RC201 , RC209, RC214, RC220, RC233, RC239, RC247, RC249 (of figure 1 ), and analogues thereof. further embodiment said cyclic structures are selected from the group consisting of a) non aromatic cyclic structures, and b) aromatic cyclic structures.
Examples of a) include but are not limited to RC032, RC057, RC088, RC091 , RC095, RC109, RC1 17, RC1 18, RC123, RC125, RC127, RC130, RC136, RC147, RC164, RC173, RC178, RC179, RC186, RC188, RC196, RC199, RC217, RC219, RC221 , RC222, RC223, RC224, RC228, RC231 , RC253, RC254, RC255, RC256, RC257,
RC258 (of figure 1 ), and analogues thereof.
Examples of b) include but are not limited to RC001 , RC006, RC014, RC014-1 RC024, RC025, RC026, RC028, RC031 , RC033, RC034, RC035, RC036, RC056, RC090, RC094, RC096, RC105, RC106,
RC107, RC108, RC1 13, RC1 16, RC121 , RC122, RC126, RC128, RC131 , RC132, RC134, RC135, RC136, RC137, RC138, RC139, RC140, RC141 , RC142, RC143, RC144, RC145, RC146, RC148, RC149, RC150, RC151 , RC153, RC154, RC155, RC156, RC157, RC158, RC159, RC160, RC161 , RC162, RC163, RC165, RC166,
RC168, RC169, RC170, RC171 , RC172, RC174, RC176, RC181 , RC182, RC183, RC184, RC185, RC189, RC190, RC191 , RC192, RC200, RC202, RC203, RC204, RC205, RC206, RC207, RC208, RC210, RC21 1 , RC212, RC213, RC215, RC216, RC218, RC225, RC226, RC227, RC227-1 , RC229, RC230, RC234, RC235, RC236,
RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC246, RC248, RC250, RC251 , RC252, RC254, RC255, RC256, RC257, RC258 (of figure 1 ), and analogues thereof.
In another embodiment wherin the inhibitory effect has been optimized while avoiding toxic side-effects, X of the general formula (II) in said non-cyclic structures is an alkyl structure. Examples thereof include but are not limited to RC029, RC030, RC037, RC038, RC040, RC089, RC090, RC091 , RC092, RC093, RC097, RC100, RC101 , RC102, RC103, RC1 14, RC1 15, RC1 19, RC120, RC124, RC180, RC193, RC194, RC195, RC197, RC198, RC201 , RC209, RC214, RC220, RC233, RC239, RC247, RC249 (of figure 1 ), and analogues thereof.
In another embodiment wherin the inhibitory effect may also be optimized while avoiding toxic side-effects, the compounds of the present invention comprises piperazines with two symmetrically placed alkyl amine chains and optionally one more substituent on the piperazine. Examples thereof include but are not limited to RC088, RC091 , RC096, RC1 13, RC121 , RC122, RC123, RC125, RC127, RC188,
RC222, RC223, RC224, RC228 (of figure 1 ), and analogues thereof.
In an important embodiment wherin the inhibitory effect is great, the compounds of the present invention comprises piperazines and diazepanes with two alkyl amine chains and optionally one more substituent on the piperazine or diazepane.
Examples thereof include but are not limited to RC088, RC091 , RC095, RC096, RC1 13, RC121 , RC122, RC123, RC125, RC127, RC188, RC222, RC223, RC224, RC228 (of figure 1 ), and analogues thereof.
In one embodiment the compounds of the present invention comprises piperazines with two asymmetrically placed alkyl amine chains and optionally one more substituent on the piperazine. Examples thereof include but are not limited to RC1 16, RC166, RC223, RC228, RC231 , RC253, (of figure 1 ), and analogues thereof.
In a further embodiment the compounds of the present invention comprises piperazine compounds comprising more than 4 amines. Examples thereof include but are not limited to RC188, RC189, RC222, RC223, RC224, RC228, RC231 , RC253 (of figure 1 ), and analogues thereof.
In yet another embodiment the compounds of the present invention comprises small benzene containing compounds and saturated analogues. Examples thereof include but are not limited to RC025, RC032, RC094, RC104, RC109, RC126, RC128, RC131 , RC132, RC137, RC138, RC139, RC140, RC141 , RC142, RC143, RC145, RC148, RC149, RC150, RC151 , RC152, RC153, RC154, RC155, RC156, RC157, RC158, RC159, RC160, RC161 , RC162, RC163, RC165, RC172, RC182, RC183, RC184, RC185, RC210, RC234, RC235, RC236, RC237, RC238, RC240, RC241 , RC242, RC243, RC244, RC245, RC248, RC255, RC256, RC257 (of figure 1 ), and analogues thereof.
In another embodiment the compounds of the present invention comprises large unbranched compounds containing aromatic rings, and two identical substituents on the ring. Examples thereof include but is not limited to RC106, RC200, RC208, RC215, RC216, RC226, RC229, RC250, RC251 , RC252, RC254, RC258 (of figure 1 ), and analogues thereof.
In another embodiment the compounds of the present invention comprises large branched compounds containing aromatic rings. Examples thereof include but is not limited to RC107, RC134, RC144, RC174, RC189, RC190, RC191 , RC202, RC203, RC204, RC205, RC206, RC207, RC210, RC21 1 , RC212, RC213, RC225, RC227, RC230 (of figure 1 ), and analogues thereof.
In another embodiment X of formula (II) of the compounds of the present invention comprises unbranched aliphatic compounds. Examples thereof include but are not limited to RC030, RC030-1 , RC093, RC101 , RC102, RC1 10, RC1 14, RC1 15, RC1 19, RC120, RC124, RC147, RC194, RC195, RC209, RC233, RC239 of figure 1 , and analogues thereof.
The inventors have found that branching of the alkyl chain may increase the efficacy of the compounds of the present invention as inhibitor of megalin and cubilin. Accordingly, in another embodiment X of formula (II) of the compounds of the present invention comprises branched aliphatic compounds. Examples thereof include but are not limited to RC032, RC038, RC109, RC1 12, RC192, RC193, RC197, RC198, RC201 , RC221 of figure 1 , and analogues thereof.
In another embodiment the compounds of the present invention comprises aminoglycoside fragments. An example thereof include but is not limited to RC179 of figure 1 , and analogues thereof Novel Polymers
In an important embodiment of the present invention the compound structure is a multimer of monomeric compounds individually defined by the general formula (I).
In yet another important embodiment of the present invention the compound is of the general formula (IX)
wherein A is independently selected from formula (I) and/or formula (II) and/or formula
(III) and/or formula (IV) and/or formula (V) and/or formula (Vl) and/or formula (VII) and/or formula (VIII) as defined above, wherein
D is a spacer, q is an integer of 1 -100, p is an integer of 1 -100. wherein said spacer may be a covalent bond, wherein said spacer may consist of from 2-12 atoms, such as C-atoms, for example from 4-10 atoms, such as C-atoms, preferably from 6-8 atoms, such as C-atoms.
Salts
In an embodiment of the present invention the compound of the general formula (I) is a pharmaceutically acceptable addition salt or hydrate of said compound, such as but not limited to bromide, chloride, fluoride, hydride, iodide, nitride, oxide, phosphide, sulfide, peroxide, borate, bromate, hypobromite, carbonate, hydrogen carbonate, bicarbonate, chlorate, perchlorate, chlorite, hypochlorite, chromate, iodate, nitrate, nitrite, phosphate, hydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, thiosulfate, hydrogen sulfate, bisulfate, sulfite, hydrogen sulfite, bisulfite, acetate, formate, oxalate, hydrogen oxalate, bioxalate, hydrogen sulfide, bisulfide, telluride, amide, thiocyanate, muriate (HCI), succinate and maleate or any combination thereof or derivatives from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydrobromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and the like.
Charge
The compounds according to the invention are capable of accepting at least one proton, more preferably at least two protons because the structure of such compounds allows cell toxicity inhibition to be manifested. Accordingly, the compounds preferably have at least one amino group or one guanidino group capable of functioning as a proton acceptor. More preferably, the compounds have two amino groups capable of functioning as a proton acceptor.
According to the invention it has been found that compounds comprising a polybasic charge distribution are particularly useful as inhibitors of induced cell toxicity. Thus, as discussed above, in an embodiment of the invention the present compound has at least 1 , such as 2 positive charges in solution at physiological pH (i.e. pH 7.4), such as at least 2 positive charges. Preferably, the compound has at least 2 positive charges, preferably at least 2 positively charged nitrogens, under physiological conditions.
By selecting the positive charges within an interval of from 1 to 300, such as 1 to 20, e.g. 1 -10, it is normally possible to block a sufficient number of binding sites on the receptor responsible for mediating induced cell toxicity, such as the receptor megalin and/or the receptor cubilin and/or a co-receptor of megalin and cubilin. This results in the inhibition of uptake of the therapeutic agent responsible for inducing cell toxicity. In one embodiment, the polybasic charge distribution has the same charge distribution as the cell toxicity inducing therapeutic agent.
In the case of the receptor cubilin and the receptor megalin, a plausible explanation why a polybasic charge distribution is advantageous may be that the binding of the aminoglycoside gentamicin to the receptor(s) is not necessarily dependent on the native conformation of the receptor, since reduction of disulfide-bridges does not significantly interfere with ligand binding. Moreover, the addition of EDTA, which depletes the presence of calcium and affects receptor stability, does not abolish binding. This indicates that the interaction between receptor and gentamicin may depend on simple ionic interactions rather than the overall conformation of the receptor.
Pharmaceutical composition
In a further aspect, the invention relates to a pharmaceutical composition comprising a compound as defined herein or a compound for which a use is described herein and pharmaceutically acceptable carriers, excipients or diluents therefore.
In an important embodiment of the present invention a compound is used for the preparation of a medicament for the prophylaxis and/or treatment of nephrotoxicity and/or ototoxicity wherein the stoichiometric ratio between a compound p and a salt q
is — wherein p may be any integer from 0 to 100 and wherein q may be any integer Q from O to 100.
A combination medicament comprising a compound as defined above and a therapeutic agent that may be an antibiotic agent, for simultaneous, separate or sequential use in therapy.
A pharmaceutical composition comprising a compound as defined above and pharmaceutically acceptable carriers, excipients or diluents therefor.
In a further embodiment the compounds as defined herin above comprise any stereochemical variation or combination thereof of the compound defined by the general formula I.
In an embodiment of the present invention, the compound L of formula I is present singularly, plurally or as a combination thereof as selected from the compounds defined herein above. Dosages
The dosage of the compound according to the present invention depends on the compound in question; however, the amount of the compound is also closely related to the therapeutic agent co-administered with the compound as well as the dosage of said therapeutic agent.
For all methods of use disclosed herein for the compounds, the daily oral dosage regimen will preferably be from about 0.1 ng/kg of total body weight to about 10 g/kg of total body weight, such as 0.1 ng/kg of total body weight, for example 0.5 ng/kg of total body weight, such as 1 ng/kg of total body weight, for example 5 ng/kg of total body weight, such as 10 ng/kg of total body weight, for example 50 ng/kg of total body weight, such as 100 ng/kg of total body weight, for example 200 ng/kg of total body weight, , such as 300 ng/kg of total body weight, for example 400 ng/kg of total body weight, such as 500 ng/kg of total body weight, for example 600 ng/kg of total body weight, such as 700 ng/kg of total body weight, for example 800 ng/kg of total body weight, such as 900 ng/kg of total body weight, for example 1 μg/kg of total body weight, such as 2 μg/kg of total body weight, for example 3 μg/kg of total body weight, such as 4 μg/kg of total body weight, for example 5 μg/kg of total body weight, such as 10 μg/kg of total body weight, for example 15 μg/kg of total body weight, such as 20 μg/kg of total body weight, for example 25 μg/kg of total body weight, such as 50 μg/kg of total body weight, for example 75 μg/kg of total body weight, such as 100 μg/kg of total body weight, for example 150 μg/kg of total body weight, such as 200 μg/kg of total body weight, for example 250 μg/kg of total body weight, such as 300 μg/kg of total body weight, for example 350 μg/kg of total body weight, such as 400 μg/kg of total body weight, for example 450 μg/kg of total body weight, such as 500 μg/kg of total body weight, for example 550 μg/kg of total body weight, such as 600 μg/kg of total body weight, for example 650 μg/kg of total body weight, such as 700 μg/kg of total body weight, for example 750 μg/kg of total body weight, such as 800 μg/kg of total body weight, for example 850 μg/kg of total body weight, such as 900 μg/kg of total body weight, for example 950 μg/kg of total body weight, such as 1 mg/kg of total body weight, such as 2 mg/kg of total body weight, for example 3 mg/kg of total body weight, such as 4 mg/kg of total body weight, for example 5 mg/kg of total body weight, such as 10 mg/kg of total body weight, for example 15 mg/kg of total body weight, such as 20 mg/kg of total body weight, for example 25 mg/kg of total body weight, such as 50 mg/kg of total body weight, for example 75 mg/kg of total body weight, such as 100 mg/kg of total body weight, for example 150 mg/kg of total body weight, such as 200 mg/kg of total body weight, for example 250 mg/kg of total body weight, such as 300 mg/kg of total body weight, for example 350 mg/kg of total body weight, such as 400 mg/kg of total body weight, for example 450 mg/kg of total body weight, such as 500 mg/kg of total body weight, for example 550 mg/kg of total body weight, such as 600 mg/kg of total body weight, for example 650 mg/kg of total body weight, such as 700 mg/kg of total body weight, for example 750 mg/kg of total body weight, such as 800 mg/kg of total body weight, for example 850 mg/kg of total body weight, such as 900 mg/kg of total body weight, for example 950 mg/kg of total body weight, such as 1.0 g/kg of total body weight, for example 1.1 g/kg of total body weight, such as 1.2 g/kg of total body weight, for example 1 .3 g/kg of total body weight, such as 1.4 g/kg of total body weight, for example 1.5 g/kg of total body weight, such as 1.6 g/kg of total body weight, for example 1.7 g/kg of total body weight, such as 1.8 g/kg of total body weight, for example 1.9 g/kg of total body weight, such as 2.0 g/kg of total body weight, for example 2.5 g/kg of total body weight, such as 3.0 g/kg of total body weight, for example 3.5 g/kg of total body weight, such as 4.0 g/kg of total body weight, for example 4.5 g/kg of total body weight, such as 5.0 g/kg of total body weight, for example 5.5 g/kg of total body weight, such as 6.0 g/kg of total body weight, for example 6.5 g/kg of total body weight, such as 7.0 g/kg of total body weight, for example 7.5 g/kg of total body weight, such as 8.0 g/kg of total body weight, for example 8.5 g/kg of total body weight, such as 9.0 g/kg of total body weight, for example 9.5 g/kg of total body weight, such as up to 10.0 g/kg of total body weight.
preferably 0.01 -350 mg/kg, more preferably 0.1 -200 mg/kg, such as 0.1 -100 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.001 to about 500 mg/kg of total body weight, preferably 0.01 -350 mg/kg, more preferably 0.1 - 200 mg/kg, such as 0.1 -100 mg/kg of total body weight.
The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a compound, alone or in combination with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage forms of the present invention depend on the particular compound or compounds employed and the effect to be achieved, as well as the pharmacodynamics associated with each compound in the host. The dose administered should be an "effective amount" or an amount necessary to achieve an "effective level" in the individual patient.
"Effective level", which is the goal of the employed dose, is defined as the concentration of the compound necessary to obtain the desired effect of using said compound. Such "effective level" may refer to the concentration of the compound in the blood, the plasma, the serum, the urin, the extracellular fluid, or in the target organ, such as the kidney or the inner ear. The "effective level" may be directly measurable using any method of analysis of compound concentration familiar to a person skilled in the art, but it may also be indirectly measured as the level obtained after dispensing a drug dose that is adequate to obtain the desired result.
Accordingly, in an embodiment the ratio of the compound administered to the therapeutic agent administered is in the interval of from 200:1 mokmol to 1 :200 mokmol, such as in the interval of from 150:1 to 1 :150 mokmol, such as in the interval of from 100:1 mokmol to 1 :50 mokmol, such as in the interval of from 50:1 mokmol to 1 :25 mokmol, such as in the interval of from 25:1 to 1 :200 mokmol, such as in the interval of from 10:1 to 1 :200 mokmol, such as in the interval of from 5:1 to 1 :200 mokmol, such as in the interval of from 25:1 to 1 :100 mokmol, such as in the interval of from 10:1 to 1 :100 mokmol, such as in the interval of from 5:1 to 1 :100 mokmol, such as in the interval of from 25:1 to 1 :50 mokmol, such as in the interval of from 10:1 to 1 :50 mokmol, such as in the interval of from 5:1 to 1 :50 mokmol, such as in the interval of from 10:1 to 1 :25 mokmol, such as in the interval of from 5:1 to 1 :10 mokmol, such as in the interval of from 25:1 to 1 :5 mokmol, such as in the interval of from 10:1 to 1 :5 mokmol.
The compound may be administered in any suitable dosage regime, but is preferably administered with the same intervals as the therapeutic agent, preferably either shortly before or during administration of the therapeutic agent.
Most of the therapeutic agents according to this invention are administered paren- terally, often intravenously. The compound according to the invention may be administered in any suitable manner according to the formulation thereof, it the compound is administered parenterally, such as intravenously as the therapeutic agent.
Medicament According to the invention the present medicament is capable of binding to the receptor megalin. In a further embodiment the medicament is capable of binding to the receptor cubilin. In yet a further embodiment the medicament is capable of binding to a co- receptor of megalin and cubilin.
In another embodiment the medicament is capable of binding to a therapeutic agent capable of binding to the receptor megalin and/or the receptor cubilin and/or a co- receptor of megalin and cubilin.
In yet another embodiment, compounds of the present invention are utilised to prevent the uptake or salvaging of circulating polyamines by rapidly proliferating cells such as tumour cells, in order to potentiate the effect of therapeutic inhibitors of polyamine biosynthesis.
Combination medicaments The present invention further relates to a combination medicament comprising the compound according to the invention in combination with a therapeutic agent. Thus, the invention further relates to a combination medicament comprising a compound as disclosed by the invention or a compound for which a use is described herein and a therapeutic agent for simultaneous, separate or sequential use in therapy, preferably antimicrobial therapy. Preferably, the therapeutic agent is any one of the above- mentioned agents.
Administration
The goal of the administration is to achieve an effective systemic level of the compound. In one embodiment of the invention this may be achieved by simultaneous administration of the compound and the medicament. In another embodiment of the present invention this may be achieved by separate administration of the compound and the medicament. The time interval between the administrations may preferably be from 0 - 30 minutes, or from 0-15 minutes, or from 0-5 minutes or even more preferably from 0 - 2 minutes or from 0 -1 minute. The main routes of drug delivery according to the present invention are intravenous, oral, and topical, as will be described below. Other drug administration methods, such as subcutaneous injection, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated.
Compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. The compounds may also be administered by inhalation, such as by intranasal and oral inhalation administration.
The mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the mammal to which the biologically active compound is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The parenteral formulations of the present invention will typically contain from about 0.05 to about 25% by weight of the active ingredient in solution, such as 0.1 to about 25% by weight of the active ingredient in solution, such as 0.2 to about 25% by weight of the active ingredient in solution, such as 0.3 to about 25% by weight of the active ingredient in solution, such as 0.4 to about 25% by weight of the active ingredient in solution, such as 0.5 to about 25% by weight of the active ingredient in solution, such as 0.6 to about 25% by weight of the active ingredient in solution, such as 0.7 to about 25% by weight of the active ingredient in solution, such as 0.8 to about 25% by weight of the active ingredient in solution, such as 0.9 to about 25% by weight of the active ingredient in solution, such as 1.0 to about 25% by weight of the active ingredient in solution, such as 2.0 to about 25% by weight of the active ingredient in solution, such as 3.0 to about 25% by weight of the active ingredient in solution, such as 4.0 to about 25% by weight of the active ingredient in solution, such as 5.0 to about 25% by weight of the active ingredient in solution, such as 6.0 to about 25% by weight of the active ingredient in solution, such as 7.0 to about 25% by weight of the active ingredient in solution, such as 8.0 to about 25% by weight of the active ingredient in solution, such as 9.0 to about 25% by weight of the active ingredient in solution, such as 10 to about 25% by weight of the active ingredient in solution, such as 1 1 to about 25% by weight of the active ingredient in solution, such as 12 to about 25% by weight of the active ingredient in solution, such as 13 to about 25% by weight of the active ingredient in solution, such as 14 to about 25% by weight of the active ingredient in solution, such as 15 to about 25% by weight of the active ingredient in solution, such as 16 to about 25% by weight of the active ingredient in solution, such as 17 to about 25% by weight of the active ingredient in solution, such as 18 to about 25% by weight of the active ingredient in solution, such as 19 to about 25% by weight of the active ingredient in solution, such as 20 to about 25% by weight of the active ingredient in solution, such as 21 to about 25% by weight of the active ingredient in solution, such as 22 to about 25% by weight of the active ingredient in solution, such as 23 to about 25% by weight of the active ingredient in solution, such as 24 to about 25% by weight of the active ingredient in solution, such as 25 to about 0.05% by weight of the active ingredient in solution, such as 24 to about 0.05% by weight of the active ingredient in solution, such as 23 to about 0.05% by weight of the active ingredient in solution, such as 22 to about 0.05% by weight of the active ingredient in solution, such as 21 to about 0.05% by weight of the active ingredient in solution, such as 20 to about 0.05% by weight of the active ingredient in solution, such as 19 to about 0.05% by weight of the active ingredient in solution, such as 18 to about 0.05% by weight of the active ingredient in solution, such as 17 to about 0.05% by weight of the active ingredient in solution, such as 16 to about 0.05% by weight of the active ingredient in solution, such as 15 to about 0.05% by weight of the active ingredient in solution, such as 14 to about 0.05% by weight of the active ingredient in solution, such as 13 to about 0.05% by weight of the active ingredient in solution, such as 12 to about 0.05% by weight of the active ingredient in solution, such as 1 1 to about 0.05% by weight of the active ingredient in solution, such as 10 to about 0.05% by weight of the active ingredient in solution, such as 9.0 to about 0.05% by weight of the active ingredient in solution, such as 8.0 to about 0.05% by weight of the active ingredient in solution, such as 7.0 to about 0.05% by weight of the active ingredient in solution, such as 6.0 to about 0.05% by weight of the active ingredient in solution, such as 5.0 to about 0.05% by weight of the active ingredient in solution, such as 4.0 to about 0.05% by weight of the active ingredient in solution, such as 3.0 to about 0.05% by weight of the active ingredient in solution, such as 2.0 to about 0.05% by weight of the active ingredient in solution, such as 1.0 to about 0.05% by weight of the active ingredient in solution, such as 0.9 to about 0.05% by weight of the active ingredient in solution, such as 0.8 to about 0.05% by weight of the active ingredient in solution, such as 0.7 to about 0.05% by weight of the active ingredient in solution, such as 0.6 to about 0.05% by weight of the active ingredient in solution, such as 0.5 to about 0.05% by weight of the active ingredient in solution, such as 0.4 to about 0.05% by weight of the active ingredient in solution, such as 0.3 to about 0.05% by weight of the active ingredient in solution, such as 0.2 to about 0.05% by weight of the active ingredient in solution, such as 0.1 to about 0.05% by weight of the active ingredient in solution, such as 0.09 to about 0.05% by weight of the active ingredient in solution, such as 0.08 to about 0.05% by weight of the active ingredient in solution, such as 0.07 to about 0.05% by weight of the active ingredient in solution, such as 0.0.06 to about 0.05% by weight of the active ingredient in solution.
Preservatives and buffers may be used. In order to minimise or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
In an embodiment of the present invention the medicament is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration or inhalation.
In a preferred embodiment of the present invention said injection of said medicament is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
In an embodiment of the present invention said injection is performed singularly.
In another embodiment of the present invention said injection is performed plurally.
In an embodiment of the present invention the duration of the medication is between 30 minutes to 24 hours.
In another embodiment of the present invention the duration of the medication is between 1 to 6 hours.
In yet another embodiment of the present invention the duration of the medication is from 6 to 72 hours.
In a further embodiment of the present invention the duration of the medication is from 1 to 14 days.
In an embodiment of the present invention the duration of the medication is from 4 to 10 days.
In a further embodiment of the present invention the duration of the medication is from 10 to 30 days. In another embodiment of the present invention the duration of the medication is from 15 to 25 days.
Binding to the receptor cubilin and/or megalin
The compounds of the present invention may all be capable of binding to the receptor megalin and/or the receptor cubilin and/or a co-receptor of megalin and cubilin. Additionally the compounds according to the invention may be capable of binding to the therapeutic agent. In case of binding to the receptor(s) it is of importance that the binding is effective in respect of blocking the binding of the therapeutic agent to the receptor. The receptor megalin for example comprises 50-150 binding sites for the therapeutic agent gentamicin and it is important for the effectiveness of the use of this invention that the compound is capable of inhibiting an effective amount of these binding sites.
Without being bound by theory the advantage of the present compound's ability of binding to the receptor cubilin and/or receptor megalin is the finding that these receptors are involved in aminoglycoside induced cell toxicity in the kidneys and the ear. Using the present compounds has an inhibitory effect on cell toxicity, such as nephrotoxicity and ototoxicity.
The compounds according to the invention may e.g. bind the receptor megalin in order to inhibit endocytosis or the receptor cubilin in order to reduce its sequestering and thereby inhibiting or reducing endocytosis.
It is also within the scope of the invention that the compound may bind to a co-receptor of megalin and cubilin.
Therapeutic agent
The therapeutic agent according to the invention may be any therapeutic agent capable of causing organ damages due to intracellular accumulation in cells in the organs. In particular, the therapeutic agent is capable of accumulating in cells in the kidneys and/or inner ear, thus causing kidney damages as well as damages to the inner ear.
Thus in a further embodiment, the induced cell toxicity is a side-effect of a therapeutic agent, wherein the therapeutic agent is selected from acebutolol, acetazolamide, acyclovir, adefovir, albumin, alclofenac, alendronate, alitretinoin, altretamine, amikacin, amiloride, aminoglutethimide, amiodarone, amoxicillin, amoxicillin/clavulanic acid, amphotericin b, amphotericin b cholesteryl sulfate complex, amphotericin b lipid complex, amphotericin b liposome, amtolmetin, aniracetam, antacids, antazoline, anthraquinone laxatives, aprotinin, arbekacin, arginine, arsenic trioxide, asparaginase, aspirin, atenolol, atovaquone, auranofin, aurothioglucose, azacitidine, azathioprine, azlocillin, aztreonam, bacampicillin, bacitracin, bemetizide, benoxaprofen, betaine, bezafibrate, bismuth subcitrate, bleomycin, boric acid, brivudine, broxuridine, bumetanide, calcifediol, calcitriol, candesartan, candesartan/hydrochlorothiazide, canrenoate, capreomycin, captopril, carbenicillin, carboplatin, carmustine, carprofen, cefaclor, cefetamet, cefixime, cefmetazole, cefonicid, cefoperazone, cefoperazone/sulbactam, cefotaxime, cefotetan, cefoxitin, cefpirome, cefsulodin, ceftazidime, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, celecoxib, cephalexin, cephaloridine, cephalothin, cephapirin, cephradine, chlortetracycline, cidofovir, cilazapril, cimetidine, ciprofibrate, cisapride, cisplatin, clarithromycin, clodronate, clofibrate, cloxacillin, cocaine, codeine, colistin, corticotropin, cosyntropin, cotrimazine, cotrimoxazole, crisnatol, cyclacillin, cyclosporine, cysteamine, decitabine, delapril, delavirdine, demeclocycline, denileukin diftitox, desflurane, dextran, diatrizoate, diazoxide, dibekacin, diclofenac, diclofenac/misoprostol, dicloxacillin, dicumarol, didanosine, dihydroergotamine, dihydroergotamine/heparin, dihydrotachysterol, dirithromycin, dopamine, doxepin, doxorubicin hydrochloride liposome, doxycycline, edetate calcium disodium, edetate disodium, emetine, enflurane, enlimomab, epinephrine, epirubicin, ergocalciferol, ergotamine, erythromycin/sulfisoxazole, erythropoietins, ethanolamine oleate, ethyl chloride, etidronate, etodolac, etomidate, etretinate, everninomycin, fadrozole, fenbufen, fenofibrate, fenoprofen, fenoterol/ipratropium, flecainide, fleroxacin, floxacillin, flupirtine, flurbiprofen, formestane, foscarnet, fosinopril, fotemustine, framycetin, furosemide, gabexate, gadopentetate dimeglumine, gallium nitrate, gemcitabine, gemfibrozil, gentamicin, glycerin, gold sodium thiomalate, guanadrel, guanethidine, guar gum, halothane, hemiacidrin, hemin, hetastarch, homoharringtonine, hyaluronidase, hydrochlorothiazide, idarubicin, ifosfamide, imatinib, imipramine, indapamide, influenza vaccine, interferon alfa-2a, interferon alfa-2b, interferon beta, natural, interferon beta- 1 b, interferon gamma, interleukin-3, interleukin-4, interleukin-6, iobenguane 1-131 , iodixanol, iohexol, iopamidol, iopanoic acid, iopentol, iopromide, iotrolan, ioversol, ioxaglate, ioxilan, ioxithalamate, irinotecan, irofulven, isepamicin, isoflurane, isoniazid, isoxicam, kanamycin, ketamine, ketoconazole, ketoprofen, ketorolac, lenograstim, levofloxacin, lincomycin, liposomal nystatin, lisinopril, lithium, lobaplatin, lomustine, Ionidamine, lornoxicam, losartan, loxapine, lymphocyte immune globulin, mannitol, mebendazole, mefenamic acid, meglumine antimoniate, melarsoprol, meropenem, mesna, metaraminol, methacycline, methicillin, methimazole, methocarbamol, methotrexate, methoxamine, metrizamide, metronidazole, mezlocillin, milrinone, miltefosine, minocycline, minoxidil, mitoguazone, mitolactol, mitomycin, mitotane, molindone, morniflumate, morphine, moxalactam, muromonab-CD3, nabumetone, nafcillin, naproxen, nedaplatin, neomycin, netilmicin, niclosamide, nifedipine, niflumic acid, nifurtimox, nisoldipine, nitroprusside, norepinephrine, norfloxacin, ofloxacin, olsalazine, oxaliplatin, oxandrolone, oxaprozin, oxolinic acid, oxytetracycline, paclitaxel, pamidronate, paramethadione, paromomycin, pefloxacin, pemetrexed, pemirolast, penicillin G, pentamidine, pentostatin, peplomycin, perindopril, phenazopyridine, phenindione, phenobarbital, phenylbutazone, phenylpropanolamine, phenytoin, phosphates, piperacillin, pirarubicin, piretanide, piroxicam, plicamycin, poloxamer-188, polymyxin B, potassium perchlorate, praziquantel, proglumetacin, propylthiouracil, pyrimethamine/sulfadoxine, quinagolide, quinapril, quinine, rabbit antithymocyte globulin, raltitrexed, ranitidine, ranpirnase, recombinant human hemoglobin, rifampin, ritodrine, ritonavir, rofecoxib, rolitetracycline, rufloxacin, salsalate, sevoflurane, silver nitrate, silver sulfadiazine, simvastatin, sodium cellulose phosphate, sodium chloride, sodium fluoride, sodium stibogluconate, spironolactone, streptokinase, streptomycin, streptozocin, sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole, sulindac, sulprostone, sultamicillin, suprofen, tacrolimus, tasonermin, teicoplanin, temafloxacin, teniposide, tenoxicam, tetracycline, thiopental, tiaprofenic acid, ticarcillin, ticrynafen, tiludronate, tiopronin, tobramycin, tocainide, tolazoline, tolmetin, torsemide, tramadol, triamterene, trimethadione, trimethaphan, trimethoprim, trimetrexate, trimipramine, troglitazone, tromethamine, typhoid vaccine, valsartan, vancomycin, zolimomab aritox, zomepirac, zopiclone, antisense RNA, PNA, siRNA or derivatives thereof.
In an embodiment, the induced cell toxicity is a side-effect of a therapeutic agent, wherein the therapeutic agent is selected from the group consisting of aminoglycosides, such as arbekacin, gentamicin, kanamycin, neomycin, paramycin, ribostamycin, lividomycin, amikacin, dibekacin, butakacin, tobramycin, streptomycin, dihydrostreptomycin, sisomicin, verdamicin, netilmicin, and butikacin; cisplatin, amphotericin B, ifosfamide, polymyxin B, cyclophosphomide, methotrexate, aprotinin, ciclosporin, and valproate as well as therapeutic antibodies.
In another embodiment, the therapeutic agent is an aminoglycoside, such as gentamicin, arbekacin or kanamycin.
Also fusion proteins or fusion products used for medical treatment wherein one of the proteins is capable of binding the megalin or the receptor cubilin and/or a co-receptor of megalin and cubilin and the other protein/product causes cell toxicity when accumulating in the cells, may be used. In particular fusion products, wherein one part of the product is an antibody or IgG light chain, both capable of unspecifically binding to cubilin, and the other part of the product is cytotoxic, such as cancer treatment, may be co-administered with a compound according to the present invention in order to reduce organ damage, in particular kidney damage.
In another important embodiment of the present invention the therapeutic agent causing nephrotoxicity and/or ototoxicity is an aminoglycoside.
In one embodiment, the compounds of the present invention are used for treatment of cancer other than leukemia or breast cancer. Examples
The following are non-limiting examples illustrating the invention.
Example 1 : Mice were injected intravenously with doses (5 mg/kg) of gentamicin with or without 4 μg RC1 12. After 120 minutes, the animals were sacrificed and the kidneys removed. The amount of 3H-gentamicin accumulating in the tissues was determined and expressed as % of total tracer injected. The results are illustrated in figure 2.
Example 2: Male mice (e.g. 83 SPF BomTac:NMRI from Taconic Europe A/S) were used for the experiments. After acclimatization the animals were approximately 5 weeks old. They were fed a diet of Altromin 1314 Fortified and had free access to drinking water. Mice were injected intravenously with a relevant dose of antagonist in PBS (volume 0.2 ml) followed by an intravenous injection with a mixture of 3H labelled gentamicin (GE Healthcare) and 5 mg/kg cold gentamicin (volume 0.2 ml, approx 10,000,000 cpm/ml, the dose of cold gentamicin corresponds to a clinical relevant dose for humans) . A control group was administered PBS without antagonist prior to gentamicin administration. After 24 hours, the animals were sacrificed and the kidneys removed. The amount of 3H-gentamicin accumulating in the kidney tissue was determined. Inhibition of gentamicin uptake was expressed as percentage reduction compared to the control group. The number of animals per group was at least 3 in all experiments. Results are displayed for selected compounds in table 2 below.
Table 2: In vivo data in mice
[ Comfiύurtd Dose Cm$/toj) I Reduction {%) RC038 40 12 RC093 40 27 RC109 14 1 1 RC1 12 2 27 RC123 120 63 RC 144 2 27 RC 174 4 44 RC188 12 83 RC190 12 60 RC191 2 45 RC193 12 55 RC198 12 39 RC201 12 40 RC203 1 ,2 16 RC204 4 28 RC208 12 43 RC215 12 39 RC216 40 31 RC222 40 41 RC223 12 61 RC224 120 52 RC225 12 65 RC226 40 62 RC227 12 59 RC228 40 59 RC234 4 18 RC258 64 7
Example 3: In vitro testing of compounds Gentamicin-inhibitor interactions were assessed by surface plasmon resonance (SPR) analysis on a Biacore 2000 instrument (Biacore, Uppsala, Sweden). Megalin purified from rabbit kidneys as described in Birn et al. (J. Biol. Chem., 1997, Vol. 272, No. 42, 26497-26504) was immobilized in a concentration of 28-40 fmol/mm3. Samples were dissolved in 10 mM Hepes, 150 mM NaCI, 1.5 mM CaCI2, 1 mM EGTA, 0.005 % Tween-20 pH 7.4. The same buffer was used as running buffer. Re-generation of the sensor chip after each analysis cycle was performed with 1 .6 M glycine-HCI buffer pH 3.0. The Biacore response is expressed in relative response units (RU) i.e. the difference in response between protein and control flow channel. Samples contained 1 mM gentamicin and 0-10 mM or 0-20 mM inhibitor. The response was read at maximum and corrected for contribution of the inhibitor response. The experiment examines the inhibiting effect of comounds of the present invention. The results are displayed in figure 1 .
Description of the Drawings
Figure 1
Examples of compounds used in the invention. Also displayed, if present are inhibition of gentamicin binding to immobilized megalin as assessed by surface plasmon resonance.
Figure 2
Inhibition of renal uptake of Gentamicin in the mouse model by administration of
RC1 12.

Claims

Claims
1 . Use of a compound comprising a structure of the general formula (I):
wherein m is an integer between 1 -100, and L is of the general formula (II):
wherein X is a bond or a C1 -12 alkyl or an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyl comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O)0-2 or carbonyl, and
wherein n is an integer between 1 and 12, and
wherein any component of X may individually be substituted with Z, j times wherein j is an integer from 1 to 12 and wherein Z is a substituent to X of the general formula (III):
Ri
R4 N R2
R3
and wherein each substituent Z may exist in a copies wherein a is an integer from 1 to 12, wherein the optional substituents R1, R2, R3 and R4 individually are selected from a bond to X, or a bond to R1, or a bond to R2, or a bond to R3, or a bond to R4, or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (Ci-12)-alkyl-aryl, (Ci-i2)-alkoxyaryl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, guanidino, nitro, O-alkyl, O-acyl, hydroxyalkyl, aminoalkyl, aminopolyalkyl, alkylamin, sucrose, fructose, glucose, galactose, maltose, lactose, mannose or wherein Ri is a hydrogen, R2 is 1 -imino- aminomethyl and R3 , selected from any of the above, connecting the thus formed guanidino group to X, wherein any of the substituents Ri, R2, R3 or R4, optionally may be substituted individually at least once, wherein the substituents are selected from: hydrogen,
O, OH, phenyl, amine (NH2), imine (NH), aminoalkyl, aminopolyalkyl, alkylamin, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, guanidino, nitro, sucrose, fructose, glucose, galactose, maltose, lactose or mannose, wherein at most 50% of the carbons comprised by Z is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R1, R2, R3 and R4 can be a bond connecting to X wherein any component of X optionally may be substituted with Y, k times wherein k is an integer between O and 12 and wherein Y is a substituent described by the general formula (IV):
R6
K5 Kg ^~^~ Ky
R8
and wherein each substituent Y may exist in b copies wherein b is an integer from 1 to 12, wherein the optional substituents R5, R6, R7, Rs and R9 individually are selected from a bond to X or a bond to R5, or a bond to R6, or a bond to R7, or a bond to R8, or a bond to R9, or a hydrogen, N, O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, (C1-12)-alkyl-aryl, (C^^-alkoxyaryl, heteroaryl-(C1. 12)-alkyl, heterocyclyl-(C1.12)-alkyl, alkylated cycloalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, nitro, Oalkyl, Oacyl, hydroxyalkyl, aminoalkyl, aminopolyalkyl, alkylamin, guanidino, sucrose, fructose, glucose, galactose, maltose, lactose and mannose, wherein R5, R6, R7, R8 and R9 optionally are individually substituted at least once, wherein the substituents are selected from: O, OH, phenyl, amine (NH2), imine
(NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(Ci- i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, carbonyl, trifluoromethyl, cyano, amino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, guanidino, sucrose, fructose, glucose, galactose, maltose, lactose or mannose
wherein any of the carbons comprised by Y is optionally replaced by oxygen, nitrogen, sulphur, or silicon, or wherein the individually optional substituents on R5, R6, R7 and R8 can be a bond connecting to X, or wherein one or more of the optional substituents R5, R6, R7 and R8 individually or in conjunction are optionally linked to one or more of the optional substituent(s) R1, R2, R3, R4, R5, R6, R7, R8, R9 and/or to N of formula III and/or to X of formula (II) and or to one of said optional substituents of said R1, R2, R3, R4, R5, R6, R7, R8, R9 thereby forming one or more rings,
wherein X is a bond linking R2 to R5 to R9 that may be a N linked to R8 to R3 thus forming a ring Q, said Q being a piperazine or piperidine ring, thereby forming the general formula V.
Ri
R4 Q R6
R7 (V)
wherein R1, R4, R6 and R7 are optional substituents as defined, wherein the general formula I comprises one ore more amino groups individually selected from primary or secondary or tertiary amines or where the amino group optionally have a further substituent attached thus forming a quaternary ammonium, with the proviso that if X of formula (II) is phenyl then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or ethylamine or 2-amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or 1 ,2,2,5,5-pentamethylpyrrolidine,
and with the proviso that if X of formula (II) is cyclohexane then Z and Y are not both methylamino or para-oriented amino groups or N-methylpiperidine or diamidinyl or methylguanidine or 2-amino-1 -hydroxyethyl or methyldiethanolamine or trans-oriented primary amines or allylpyrrole or
1 ,2,2,5,5-pentamethylpyrrolidine
and the proviso that if X of formula (II) is phenyl or cyclohexane Z is not methylamine while Y is ethylamine or an amidino group or 2-amino-1 - hydroxyethyl, and Y is not methylamine while Z is ethylamine or an amidino group,
and the proviso that if X is a bond then Z and Y are not both 4-substituted piperidine,
and the proviso that if X is C1 , then Z and Y are not both 4-aminocyclohexyl,
and with the proviso that if Q of formula (V) is N,N'-disubstituted piperazine then the substituting groups are not N-methyl and C2-C4-alkylamine respectively or N,N-dimethyl and C2-C4-alkylamine respectively,
and the proviso that if Q is N-monosubstituted piperazine, then neither R1 nor R4 nor R6 nor R7 is pyridine or C2-3-alkylamine or 4-aminophenyl.
and the proviso that if Q is a piperidine, then R1, R4, R6 and R7 are not selected among N-linked C(2-3)-alkylamine and a para-oriented amino group respectively, nor among N-linked hydrogen and para-oriented C(2-3)-alkylamine respectively,
and the proviso that if X of formula (II) is tetrahydrofurane-3,4-diole then both Z and Y are neither C^alkylamine nor C(1-2)alkylguanidine, and the proviso that if X of formula (II) is 5-amino-6-methoxy-tetrahydro-2H- pyran-3,4-diol then Z is not a C^alkylamine while Y is unsubstituted,
and the proviso that X is not 2,3 ,4,5-tetrahydroxyhexane while Z and Y are both amine,
and the proviso that if X is a C^alkyl or a N-propyl-N-pentylamine Z and Y are not both amine,
and the proviso that if X is a 1 ,4-butanediamine Z and Y are not both 3-aminopropyl
and the proviso that if X is a C(1_8)alkyl then both Z and Y are not primary amines
or a pharmaceutically acceptable addition salt or hydrate thereof
for the manufacture of a medicament for the prophylaxis and/or treatment of nephrotoxicity and/or ototoxicity.
2. The use according to claim 1 , wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members and 0 to 4 heteroatoms in each ring.
3. The use according to claim 1 , wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 5-6 ring members and 1 or 2 heteroatoms in each ring.
4. The use according to claim 1 , wherein X is an aromatic or a carbocyclic structure having 1 -3 rings, 5-6 ring members and no heteroatoms in each ring.
5. The use according to claim 2, wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -2 rings, 3-8 ring members in each and having 0 to 3 heteroatoms, wherein each ring optionally is substituted j times by Z and k times by Y of formula (II).
6. The use according to claim 2, wherein X is an aromatic, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 ring with 4-7 ring members and having 0 to 3 heteroatoms, said ring optionally being substituted j times by Z and k times by Y of formula.
7. The use according to claim 2, wherein X is selected from the group consisting of cyclopentyl, furan, thiophene, pyrrole, imidazole, oxazole, and pyrrolidene, preferably the group consisting of furan and pyrrole.
8. The use according to claim 2, wherein X is selected from the group consisting of pyridine, pyrimidine, cyclohexyl, and phenyl, preferably cyclohexyl and phenyl.
9. The use according to claim 2, wherein
X is an aromatic, a heteroaromatic or a 5 or 6 membered saturated ring containing 0-2 oxygen atoms, optionally substituted according to claims at least once, wherein the substituents are selected from O, OH, phenyl, halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(d-i2)-alkyl, heteroaryl-(d-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, nitro, Oalkyl, Oacyl, aminoalkyl, aminopolyalkyl, alkylamin, sucrose, fructose, glucose, galactose, maltose, lactose and mannose
R1, R2, R3, R4 of the Z-group is a C1 -12 alkyl bond connecting to X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (C1_12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose, maltose, lactose and mannose wherein any of the carbons in said C1 -12 alkyl is optionally replaced by oxygen, nitrogen, sulphur, or silicon,
R5, R6, R7, R8 and R9 of the Y-group is a C1 -12 alkyl bond connecting to X, optionally substituted at least once, wherein the substituents are selected from O,
OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl-(d-i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose, maltose, lactose and mannose wherein any of the carbons in said C1 -12 alkyl is optionally replaced by oxygen, nitrogen, sulphur, or silicon,
optionally further substituted one or more times with C, S, N, O, OH, phenyl, amine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl- (Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose,
10. The use according to claim 2 or 12, wherein X is an aromatic, carbocyclic, a heterocyclic or a heteroaromatic structure having 1 ring with 6 ring members and having O to 1 heteroatoms, said ring optionally being substituted.
1 1 . The use according to claim 2, wherein X is a dicyclohexylmethane.
12. The use according to claim 2 or 12, wherein X comprises a heterocyclic ring comprising at least one oxygen atom.
13. The use according to claim 15, wherein the compound comprises a structure of the formula Vl:
wherein Z and Y are substituents according to claim 1
14. The use according to claim 15 or 16, wherein the compound comprises a structure of the formula VII:
wherein Z and Y are substituents according to claim 1 .
15. The use according to any of claims 15 to 17, wherein the compound comprises a structure of the formula VIII:
wherein Z and Y are according to claim 1.
16. The use according to any of claims 15-18, wherein at least one of the Y groups is H and at least one of the Y groups is OH.
17. The use according to any of claims 15-19, wherein one of the Z groups comprises a guanidine group.
18. The use according to any of claims 15-20, wherein both Z groups comprise a guanidine group.
19. The use according to any of the preceding claims, wherein Ri or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (C1_12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
20. The use according to any of the preceding claims wherein R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C3-12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-
(Ci-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
21. The use according to any of the preceding claims, wherein Ri or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -10 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (C1_12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
22. The use according to any of the preceding claims, wherein R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -8 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (Ci-i2)-alkyl, heteroaryl-(d-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
23. The use according to any of the preceding claims, wherein R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -6 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (C1_12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
24. The use according to any of the preceding claims, wherein Ri or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 -4 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (Ci-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
25. The use according to any of the preceding claims, wherein R1 or R2 or R3 or R4 of the Z-group is a linker to X wherein said linker is a bond, or C1 or a C2 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1.12)-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1.12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
26. The use according to any of the preceding claims, wherein Ri is a C1 or C2 alkyl, substituted at least once with an imine group or substituted at least once with an OH group.
27. The use according to any of the preceding claims, wherein Ri or R2 or R3 or R4 is C1.
28. The use according to any of claims 1 to 25, wherein R1 or R2 or R3 or R4 is a bond.
29. The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
30. The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C3-12 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
31 . The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -10 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-12)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
32. The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -8 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
33. The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -6 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(Ci-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
34. The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or R9 of the Y-group is a linker to X wherein said linker is a bond, or C1 -4 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1-12)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
35. The use according to any of the preceding claims, wherein R5 or R6 or R7 or R8 or
R9 of the Y-group is a linker to X wherein said linker is a bond, or a C1 or C2 alkyl, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl-(d-i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
36. The use according to claim 40, wherein R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl, substituted at least once with an imine group or substituted at least once with an OH group.
37. The use according to any of the preceding claims, wherein Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are C1 .
38. The use according to any of claims 1 to 41 , wherein Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond.
39. The use according to any of the preceding claims, wherein R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond or a C1 -12 alkyl linker to X, said linker optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (C^^-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1.12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
40. The use according to any of the preceding claims, wherein Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond or a C2-8 alkyl linker to X, said linker optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (Ci-i2)-alkyl, heteroaryl-(Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
41. The use according to any of the preceding claims, wherein R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a bond or C4-6 alkyl linker X, optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-(C1_i2)-alkyl, heteroaryl- (Ci-i2)-alkyl, heterocyclyl-(Ci-i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
42. The use according to any of the preceding claims, wherein Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl linker to X, said alkyl being optionally substituted at least once, wherein the substituents are selected from O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl- (Ci-i2)-alkyl, heteroaryl-(Ci_i2)-alkyl, heterocyclyl-(Ci_i2)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, nitro, sucrose, fructose, glucose, galactose or maltose.
43. The use according to any of the preceding claims, wherein R1 and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a C1 or C2 alkyl linker to X, said linker being substituted at least once with an imine group or substituted at least once with an OH group.
44. The use according to any of the preceding claims, wherein Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R8 and/or R9 of the Z-group and/or the Y-group is/are a linker C1 to X.
45. The use according to any of the preceding claims, wherein one or more of Ri, R2, R3, R4, R5, R6, R7, Rs and R9 of the Z-group and/or the Y-group is/are a bond.
46. The use according to any of claim 1 to 21 , wherein R1 is a bond and R2 is a C1 -2 alkyl.
47. The use according to any of the preceding claims, wherein at least one of Ri, R2, R3, R4, R5, Re, R7, Rs and R9 of the Z-group and/or the Y-group is/are (a) hydrogen.
48. The use according to any of the preceding claims, wherein at least two of Ri , R2, R3, R4, R5, Re, R7, Rs and R9 of the Z-group and/or the Y-group are hydrogen.
49. The use according to any of the preceding claims, wherein three of Ri, R2, R3, R4 of the Z-group and four of R5, R6, R7, R8 and R9 of the Y-group are hydrogen.
50. The use according to any of claims 1 -52, wherein at least one of R4, R5 and R6 is an hydroxyalkyl, such as hydroxyethyl.
51 . The use according to any of the preceding claims, wherein Ri is linked to R2 or R3 or R4 or R5 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
52. The use according to any of the preceding claims, wherein R2 is linked to Ri or R3 or R4 or R5 or R6 or R7 or R8 or R9 forming a ring of 5-6 members.
53. The use according to any of the preceding claims, wherein R3 is linked to Ri or R2 or R4 or R5 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
54. The use according to any of the preceding claims, wherein R4 is linked to Ri or R2 or R3 or R5 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
55. The use according to any of the preceding claims, wherein R5 is linked to Ri or R2 or R3 or R4 or R6 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
56. The use according to any of the preceding claims, wherein R6 is linked to Ri or R2 or R3 or R4 or R5 or R7 or R8 or R9 thereby forming a ring of 5-6 members.
57. The use according to any of the preceding claims, wherein R7 is linked to Ri or R2 or R3 or R4 or R5 or R6 or R8 or R9 thereby forming a ring of 5-6 members.
58. The use according to any of the preceding claims, wherein R8 is linked to Ri or R2 or R3 or R4 or R5 or R6 or R7 or R9 thereby forming a ring of 5-6 members.
59. The use according to any of the preceding claims, wherein R9 is linked to Ri or R2 or R3 or R4 or R5 or R6 or R7 or R8 thereby forming a ring of 5-6 members.
60. The use according to any of the preceding claims, wherein one or more of Ri and/or R2 and/or R3 and/or R4 and/or R5 and/or R6 and/or R7 and/or R9 is a guanidine group or comprises a guanidine group.
61. The use according to any of the preceding claims, wherein two of Ri, R2, R3 and R4 of the Z-group of formula (II) are linked to X, thereby forming one or more rings.
62. The use according to any of the preceding claims, wherein two of R5, R6, R7, R8 and R9 of the Y-group of formula (II) are linked to X, thereby forming one or more rings.
63. The use according to claim 65, wherein at least one of said rings has 5 members.
64. The use according to claim 66, wherein one of either R1 or R2 or R3 or R4 of the Z- group of formula (II) is linked to X and to a non-self member among R1, R2, R3 and R4, thereby generating a ring of 6 members, further comprising an atomic bridge.
65. The use according to any of claims 65 or 67, wherein one of Ri, R2, R3 and R4 of the Z-group of formula (II) is linked to X and to one of either R5 or R6 or R7 or R8 or R9 of the Y-group of formula II, thereby generating a ring of 6 members, further comprising an atomic bridge.
66. The use according to formula (V) of claim 1 , wherein Ri and/or R4 and/or R6 and/or R7 is/are unsubstituted C1 -C12 alkyl(s).
67. The use according to formula (V) of claim 1 , wherein R1 and/or R4 and/or R6 and/or R7 is/are substituted C1 -C12 alkyl(s).
68. The use according to formula (V) of claim 1 , wherein R1 and/or R4 and/or R6 and/or R7 is/are alkylbenzene.
69. The use according to claim 67 and formula (V) of claim 1 , wherein R1 and/or R4 and/or R6 and/or R7 is/are alkylamine(s).
70. The use according to claim 67 and 69 wherein the alkylamine(s) is/are unsubstituted.
71. The use according to claim 70 and formula (V) of claim 1 , wherein R1 and/or R4 and/or R6 and/or R7 is/are alkylamine(s) individually optionally substituted once or twice or more wherein the substituents are selected from hydrogen, O, OH, phenyl, amine (NH2), imine (NH), halogen, alkyl, alkenyl or alkynyl, substituted lower alkyl, substituted lower alkenyl or alkynyl, aryl, heterocyclyl, heteroaryl, aryl-
(Ci-i2)-alkyl, heteroaryl-(C1.12)-alkyl, heterocyclyl-(C1.12)-alkyl, cycloalkylalkyl, cycloalkyl, alkoxy, carboxy, trifluoromethyl, cyano, amino, guanidino, aminoalkyl, aminopolyalkyl, alkylamin, alkylpolyamine, nitro, sucrose, fructose, glucose, galactose or maltose.
72. The use according formula (V) of claim 1 , wherein R1 and/or R4 and/or R6 and/or R7 is/are H.
73. The use according to any of the preceding claims, wherein any of R1, R4, R6 or R7 individually or in conjunction form(s) a piperazine or piperidine ring.
74. The use according to formula (V) of claim 1 , wherein one or more of any of R1, R4, R6 or R7 is H or CH3.
75. The use according to formula (V) of claim 1 , wherein any of R1, R4, R6 or R7 is a primary, secondary, tertiary or quaternary amine or a secondary, tertiary or quaternary d-^-alkylamine.
76. The use according to formula (V) of claim 1 , wherein X is a bond connecting R2 and R5.
77. The use according to any of the preceding claims, wherein X is a bond connecting R2 of the Z-group of formula (II) and R5 of the Y-group of formula I and none of R1, R3, R4, and R6, R7, R8 is linked to another substituent R1-R8.
78. The use according to claim 77, wherein R2 is a bond linked to X and R5 is C1 -12 alkyl substituted at least once with an OH group.
79. The use according to claim 77 or 78, wherein R2 is C4 alkyl substituted two, three or four times with an OH group.
80. The use according to claim 78 to 79, wherein one, two or three or all of R3, R4, R5, and R6 are hydrogen.
81. The use according to any of the preceding claims, wherein said compound has a polybasic charge distribution.
82. The use according to claim 81 , where the compound under physiological conditions has at least one positively charged nitrogen.
83. The use according to claim 81 , where the compound under physiological conditions has at least two positively charged nitrogens.
84. The use according to claim 81 , where the compound under physiological conditions has three or more positively charged nitrogens.
85. The use according to any of claims 81 to 84, wherein said positively charged nitrogens are separated by 2-100 atoms.
86. The use according to any of the preceding claims, wherein the compound does not comprise a substituted or unsubstituted piperazine structure.
87. The use according to any of the preceding claims, wherein the compound does not comprise a substituted or unsubstituted piperidine structure.
88. The use according to any of the preceding claims, wherein the compound does not comprise a ring structure having 3 nitrogen atoms.
89. The use according to any of the preceding claims, wherein the compound is capable of binding to the receptor megalin and/or the receptor cubilin.
90. The use according to any of the preceding claims, wherein the nephrotoxicity and/or ototoxicity is/are (a) side-effect(s) of a therapeutic agent, wherein said therapeutic agent is selected from the group consisting of arbekacin, capreomycin, captopril, carbenicillin, carboplatin, carmustine, carprofen, cefaclor, cefetamet, cefixime, cefmetazole, cefonicid, cefoperazone, cefoperazone/sulbactam, cefotaxime, cefotetan, cefoxitin, cefpirome, cefsulodin, ceftazidime, ceftezole, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, celecoxib, cephalexin, cephaloridine, cephalothin, cephapirin, cephradine, chlortetracycline, cidofovir, cilazapril, cimetidine, ciprofibrate, cisapride, cisplatin, clarithromycin, clodronate, clofibrate, cloxacillin, cocaine, codeine, colistin, corticotropin, cosyntropin, cotrimazine, cotrimoxazole, crisnatol, cyclacillin, cyclosporine, cyste- amine, decitabine, delapril, delavirdine, demeclocycline, denileukin diftitox, desflurane, dextran, diatrizoate, diazoxide, dibekacin, diclofenac, diclofenac/misoprostol, dicloxacillin, dicumarol, didanosine, dihydroergotamine, dihydroergotamine/heparin, dihydrotachysterol, dirithromycin, dopamine, doxepin, doxorubicin hydrochloride liposome, doxycycline, edetate calcium disodium, edetate disodium, emetine, enflurane, enlimomab, epinephrine, epirubicin, ergocalciferol, ergotamine, erythromycin/sulfisoxazole, erythropoietins, ethanolamine oleate, ethyl chloride, etidronate, etodolac, etomidate, etretinate, everninomycin, fadrozole, fenbufen, fenofibrate, fenoprofen, fenoterol/ipratropium, flecainide, fleroxacin, floxacillin, flupirtine, flurbiprofen, formestane, foscarnet, fosinopril, fotemustine, framycetin, furosemide, gabexate, gadopentetate dimeglumine, gallium nitrate, gemcitabine, gemfibrozil, gentamicin, glycerin, gold sodium thiomalate, guanadrel, guanethidine, guar gum, halothane, hemiacidrin, hemin, hetastarch, homoharringtonine, hyaluronidase, hydrochlorothiazide, idarubicin, ifosfamide, imatinib, imipramine, indapamide, influenza vaccine, interferon alfa-2a, interferon alfa-2b, interferon beta, natural, interferon beta-1 b, interferon gamma, interleukin-3, interleukin-4, interleukin-6, iobenguane 1-131 , iodixanol, iohexol, iopamidol, iopanoic acid, iopentol, iopromide, iotrolan, ioversol, ioxaglate, ioxilan, ioxithalamate, irinotecan, irofulven, isepamicin, isoflurane, isoniazid, isoxicam, kanamycin, ketamine, ketoconazole, ketoprofen, ketorolac, lenograstim, levofloxacin, lincomycin, liposomal nystatin, lisinopril, lithium, lobaplatin, lomustine, Ionidamine, lornoxicam, losartan, loxapine, lymphocyte immune globulin, mannitol, mebendazole, mefenamic acid, meglumine antimoniate, melarsoprol, meropenem, mesna, metaraminol, methacycline, methicillin, methimazole, methocarbamol, methotrexate, methoxamine, metrizamide, metronidazole, mezlocillin, milrinone, miltefosine, minocycline, minoxidil, mitoguazone, mitolactol, mitomycin, mitotane, molindone, morniflumate, morphine, moxalactam, muromonab-CD3, nabumetone, nafcillin, naproxen, nedaplatin, neomycin, netilmicin, niclosamide, nifedipine, niflumic acid, nifurtimox, nisoldipine, nitroprusside, norepinephrine, norfloxacin, ofloxacin, olsalazine, oxaliplatin, oxandrolone, oxaprozin, oxolinic acid, oxytetracycline, paclitaxel, pamidronate, paramethadione, paromomycin, pefloxacin, pemetrexed, pemirolast, penicillin G, pentamidine, pentostatin, peplomycin, perindopril, phenazopyridine, phenindione, phenobarbital, phenylbutazone, phenylpropanolamine, phenytoin, phosphates, piperacillin, pirarubicin, piretanide, piroxicam, plicamycin, poloxamer-188, polymyxin B, potassium perchlorate, praziquantel, proglumetacin, propylthiouracil, pyrimethamine/sulfadoxine, quinagolide, quinapril, quinine, rabbit antithymocyte globulin, raltitrexed, ranitidine, ranpirnase, recombinant human hemoglobin, rifampin, ritodrine, ritonavir, rofecoxib, rolitetracycline, rufloxacin, salsalate, sevoflurane, silver nitrate, silver sulfadiazine, simvastatin, sodium cellulose phosphate, sodium chloride, sodium fluoride, sodium stibogluconate, spironolactone, streptokinase, streptomycin, streptozocin, sulfamethoxazole, sulfasalazine, sulfinpyrazone, sulfisoxazole, sulindac, sulprostone, sultamicillin, suprofen, tacrolimus, tasonermin, teicoplanin, temafloxacin, teniposide, tenoxicam, tetracycline, thiopental, tiaprofenic acid, ticarcillin, ticrynafen, tiludronate, tiopronin, tobramycin, tocainide, tolazoline, tolmetin, torsemide, tramadol, triamterene, trimethadione, trimethaphan, trimethoprim, trimetrexate, trimipramine, troglitazone, tromethamine, typhoid vaccine, valsartan, vancomycin, zolimomab aritox, zomepirac, zopiclone, antisense RNA, RNA, siRNA or derivatives thereof.
91 . The use according to any of the preceding claims, wherein the nephrotoxicity and/or ototoxicity is a side-effect of a therapeutic agent, wherein the therapeutic agent is an aminoglycosides selected from the group consisting of arbekacin, gentamicin, kanamycin, neomycin, paramycin, ribostamycin, lividomycin, amikacin, dibekacin, butakacin, tobramycin, streptomycin, dihydrostreptomycin, sisomicin, verdamicin, netilmicin and butikacin.
92. The use according to any of the preceding claims, wherein the nephrotoxicity and/or ototoxicity is/are a side-effect of a therapeutic agent, said therapeutic agent is selected from the group consisting of cisplatin, amphotericin B, ifosfamide, polymyxin B, cyclophosphomide, methotrexate, aprotinin, ciclosporin, valproate and therapeutic antibodies.
93. A compound having the general formula of
wherein A is independently selected from formula (I) and/or formula (II) and/or formula (III) and/or formula (IV) and/or formula (V) and/or formula (Vl) and/or formula (VII) and/or formula (VIII) as defined in any one of the preceding claims, wherein D is a spacer, q is an integer of 1 -100, p is an integer of 1 -100.
94. The compound according to claim 93, wherein the spacer is a covalent bond.
95. The compound according to claim 93, wherein the spacer consists of from 2-12 atoms, such as C-atoms, for example from 4-10 atoms, such as C-atoms, preferably from 6-8 atoms, such as C-atoms.
96. Use of a compound as defined in claim 95 for the preparation of a medicament for the prophylaxis and/or treatment of nephrotoxicity and/or ototoxicity as defined in any of claims 1 to 95.
97. The use according to any of the preceding claims of a pharmaceutically acceptable addition salt or hydrate of said compound.
98. The use according to claim 97 wherein said addition salt or hydrate are selected from bromide, chloride, fluoride, hydride, iodide, nitride, oxide, phosphide, sulfide, peroxide, borate, bromate, hypobromite, carbonate, hydrogen carbonate, bicarbonate, chlorate, perchlorate, chlorite, hypochlorite, chromate, iodate, nitrate, nitrite, phosphate, hydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, thiosulfate, hydrogen sulfate, bisulfate, sulfite, hydrogen sulfite, bisulfite, acetate, formate, oxalate, hydrogen oxalate, bioxalate, hydrogen sulfide, bisulfide, telluride, amide, thiocyanate, muriate (HCI), succinate and maleate or any combination thereof or derivatives from nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydrobromic, hydriodic, hydrofluoric, phosphorous, or salts derived from nontoxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids such as sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chloro- benzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluene- sulfonate, phenylacetate, citrate, lactate, tartrate and methanesulfonate.
99. The use according to any of claims 97 to 98 wherein the stoichiometric ratio
between compound p and salt q is — wherein p may be any integer from 0 to 100
Q and wherein q may be any integer from 0 to 100.
100. A combination medicament comprising a compound as defined in any of the claims 1 to 99 and a therapeutic agent that may be a bacteriostatic agent, for simultaneous, separate or sequential use in therapy.
101. The use according to claim 100 wherein the therapeutic agent and the compound according to any of claims 1 to 99 are administered sequentially wherein the time interval between the administrations range from 0 and 30 minutes such as from 0-15 minutes, for example from 0-5 minutes, such as from 0 - 2 minutes, for example from 0 -1 minute.
102. A pharmaceutical composition comprising a compound as defined in any of the preceding claims and pharmaceutically acceptable carriers, excipients or diluents therefor.
103. The use of any of the preceding claims comprising any stereo-chemical variation or combination thereof of the compound defined by the general formula I.
104. The use according any of the preceding claims wherein the compound L of formula I is present singularly, plurally or as a combination thereof as selected from the compounds defined in any of the preceding claims.
105. The medicament according to any of the preceding claims, for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.
106. The medicament according to claim 105, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.
107. The use according to claim 106 wherein said injection is performed singularly.
108. The use according to claim 106 wherein said injection is performed plurally.
109. The medicament according to claim 105 wherein administration occurs at intervals of 30 minutes to 24 hours.
1 10. The medicament according to claim 105, wherein administration occurs at intervals of 1 to 6 hours.
1 1 1. The medicament according to claim 105, wherein the duration of the treatment is from 6 to 72 hours.
1 12. The medicament according to claim 105, wherein the duration of the treatment is from 1 to 14 days.
1 13. The medicament according to claim 105, wherein the duration of the treatment is from 4 to 10 days.
1 14. The medicament according to claim 105, wherein the duration of the treatment is from 10 to 30 days.
1 15. The medicament according to claim 105, wherein the duration of the treatment is from 15 to 25 days.
1 16. The medicament according to any of the preceding claims, wherein the dosage of the medicament range from about 0.1 ng/kg of total body weight to about 10 g/kg of total body weight.
1 17. Use of the medicament according to any of the preceeding claims for the treatment of a disease or disorder involving rapidly proliferating cells.
1 18. The use of claim 1 17 wherein the disease or disorder is cancer.
EP08715624A 2007-03-20 2008-03-19 Amino derivatives to prevent nephrotoxicity and cancer Withdrawn EP2139461A2 (en)

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