WO2002094270A2 - Mip-1 alpha receptor ligands - drugs for t-cell mediated and autoimmune diseases - Google Patents

Mip-1 alpha receptor ligands - drugs for t-cell mediated and autoimmune diseases Download PDF

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WO2002094270A2
WO2002094270A2 PCT/CA2002/000711 CA0200711W WO02094270A2 WO 2002094270 A2 WO2002094270 A2 WO 2002094270A2 CA 0200711 W CA0200711 W CA 0200711W WO 02094270 A2 WO02094270 A2 WO 02094270A2
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substituted
unsubstitued
formula
ccr
cycloalkyls
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PCT/CA2002/000711
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French (fr)
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WO2002094270A3 (en
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Geeta Saxena
Christopher R. Tudan
Hassan Salari
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Chemokine Therapeutics Corporation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to therapeutic organic compounds and uses thereof, including the treatment of MIP-1 alpha receptor mediated diseases.
  • Chemokines are a diverse group of small secreted basic proteins, that regulate the chemotactic migration and activation of a number of different leukocytes, particularly in the context of activation of the immune response during inflammatory conditions.
  • Examples of cells that have been shown to chemotactically respond to and become activated by chemokines include a variety of leukocytes, such as neutrophils, eosinophils, basophils, monocytes, macrophages, as well as B lymphocytes and different types of T lymphocytes.
  • leukocytes such as neutrophils, eosinophils, basophils, monocytes, macrophages, as well as B lymphocytes and different types of T lymphocytes.
  • chemokines may be subdivided into four subfamilies, CXC, CC, C and CX 3 C, depending on the position of the first two cysteine residues. At least 16 chemokine receptors, including nine CC-chemokine receptors and five CXC-chemokine receptors, have been identified.
  • the CC chemokine family includes macrophage inflammatory protein (MIP) - 1 alpha, MlP-lbeta, RANTES (regulated on activation normal T-cell expressed and secreted), monocyte chemotactic protein (MCP)-l, -2, -3, and —4.
  • MIP macrophage inflammatory protein
  • MCP monocyte chemotactic protein
  • -2, -3, and —4 The CC chemokines are generally chemotactic for T cells, monocytes, basophils, and eosinophils, but not neutrophils. These chemokmes are thought to attract leukocytes by binding to the seven transmembrane-spanning G-protein coupled receptors CCR-1 through CCR-8.
  • CC chemokine receptors that have been cloned include: CC chemokine receptor-1 (CCR-1), which recognizes MIP-1 alpha and RANTES, CCR-2 which recognizes MCP-1; CCR-3 which recognizes eotoxin; CCR-4, which recognizes MIP-1 alpha, RANTES and MCP-1; and CCR-5, which recognizes MlP-lalpha, MlP-lbeta, and RANTES.
  • CCR-1 CC chemokine receptor-1
  • Chemokines, and chemokine receptors are thought to mediate (i.e. play a role in) a variety of disease states, including the pathogenesis of chronic inflammatory diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA).
  • MS multiple sclerosis
  • RA rheumatoid arthritis
  • MIP-1 alpha may play a role in the pathology of T-cell mediated autoimmune diseases such as EAE.
  • MIP- 1 alpha is reportedly elevated in chronic interstitial lung disease and also exerts a prominent effect on the persistent recruitment of mononuclear cells into the inflamed lung. It has also been suggested that MIP-1 alpha is not only important in monocyte recruitment during Thl type inflammatory lesion development, but also has a role in eosinophil recruitment during a Th2 type allergic airway response.
  • T-cell mediated diseases including autoimmune diseases, inflammation, multiple sclerosis, chronic interstitial lung disease, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, allergy, contact hypersensitivity, psoriasis, systemic lupus erythematosus, and diseases mediated by superantigen toxins such as staphylococcal enterotoxin B, and toxic shock syndrome toxin 1.
  • MIP-1 alpha The severe bone destruction commonly associated with multiple myeloma (MM) is reportedly due to increased osteoclast (OC) activity induced by as yet unidentified factor(s) produced by the MM cells. It's been reported that MIP-1 alpha, is produced by MM cells and that its levels are elevated in bone marrow plasma of MM patients compared with other hematological malignancies and normal controls. It has been shown that MIP- 1 alpha increases OC formation and bone resorption in vivo when expressed adjacent to bone surfaces. Evidence such as this has led to the suggestion that MlP-lalpha plays an important role in bone destruction, such as the pathogenesis of MM.
  • MIP-1 alpha has been shown to inhibit T-cell infection by the human immunodeficiency virus (HIV), the agent responsible for causing human Acquired Immune Deficiency Syndrome (AIDS).
  • HIV human immunodeficiency virus
  • RANTES, MIP- 1 alpha, and MIP-1 beta have shown a dose-dependent ability to inhibit specific strains of HIV from infecting cultured T-cell lines.
  • the chemokine receptor CCR-5 reportedly binds MIP-1 alpha, MIP-1 beta, and RANTES, and constitutes a major co-receptor allowing infection of CD4 + T lymphocytes, macrophages, and microglial cells by macrophage-tropic strains of human and simian immunodeficiency virus.
  • a synthetic truncated CCR-5 molecule that was capable of ligand binding but not of transducing signals by means of Ca 2+ flux or chemotaxis, has been shown to inhibit CCR-5 dependent HIV infection, suggesting that CCR-5 ligands may inhibit HIV infection.
  • Sempervirine is a pentacyclic anhydronium indole alkaloid (2,3,4,13-tetrahydro-lH-benzo[g]indolo[2,3-a]quinolizin-6- ium; CAS Registry No. 6882-99-1; or 3,4,5,6,14,15,20,21-octadehydroyohimbanium; C 1 H 16 N 2 , molecular weight: 272.35). None of the above patents reported the use of 3 A5,6 4,15,20,21-octadehydrovohimbanium in the treatment of chemokine mediated diseases.
  • Compound 1 sempervirine (also identified herein as CTCM111)
  • Sempervirine may be isolated from Gelsemium sempervirens (Loganiaceae) Ait. F., (Carolina jessamine) commonly known as yellow jessamine. Sempervirine, which is a quinolizin derivative in the beta-carboline class of alkaloids, may also be prepared using a variety of known synthetic approaches.
  • the invention relates to compounds capable of binding to the macrophage inflammatory protein - one alpha (MIP-1 alpha) receptors CCR-1, CCR-4, and CCR-5.
  • MIP-1 alpha macrophage inflammatory protein - one alpha
  • the invention provides methods for the use of such compounds in the modulation of processes mediated by such receptors, including in the treatment of diseases, such as diseases mediated by MIP-1 alpha, CCR-1, CCR-4 or CCR- 5.
  • Pharmaceutical compositions of the compounds of the invention are accordingly provided in alternative aspects of the invention.
  • the invention relates to methods of using pentacyclic compounds of formula (I), (II), (III), (IV), (V) or (VI), or pharmaceutically acceptable salts thereof, to treat, or to formulate a medicament for the treatment of, a chemokine mediated disease state:
  • Form II e.g., sempervirine and its salt (wherein X represents a counterion of the salf of the compound, and H is 0 or an integer enumerating the counterion).
  • a may be 0 or an integer from 1 to 4;
  • b may be 0 or an integer from 1 to 8;
  • c may be 0 or an integer from 1 to 2
  • d may be 0 or an integer from 1 to 2
  • X is a counterion, and may for example be Cl “ , Br “ , T or NO 3 " .
  • "a”, "b”, “c” or “d” are greater than 1, the relevant substituents need not be the same, so that for example if a-2 in the substituent (R 2 , the two Rl groups may be the same or different.
  • ring A may be aromatic or aliphatic.
  • Rings B, C and D are hetrocyclic with 'N' substituents, as shown.
  • Ring C and D may be aromatic or aliphatic or in other words, anhydro or dehydro at one or more 'C positions in the ring.
  • Ring E may be aliphatic or aromatic, with or with out hetero-atom substitutions. Where a ring has more than one site for attachment of substitutents, the substituent thereon may be a cyclic substituent that attaches to the ring at more than one position.
  • R ⁇ and R 2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C 1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C 3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C 2-6 alkenyls; substituted or unsubstitued alkynyls, such as C 2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstituted heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls;
  • R 3 , R 4 , R 5 , R 6j R ; R 8 , R 9; R 10> and R11, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstitued alkyls, such as CM O alkyls; substituted or unsubstitued cycloalkyls, such as C 3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C 2-6 alkenyls; substituted or unsubstitued alkynyls, such as C 2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides;
  • compounds of the invention may be used to treat diseases mediated by a chemokine or a chemokine receptor.
  • the chemokine may for example be selected from the group consisting of: MIP-1 alpha, and chemokines that bind to a chemokine receptor in a mammal selected from the group such as CCR-1, CCR-4 and CCR-5.
  • the chemokine receptor may be selected from the group consisting of CCR-1, CCR-4 and CCR-5
  • the invention provides for the use of compounds of the invention in the treatment of diseases selected from the group consisting of inflammation, chronic and acute inflammation, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthrifis, autoimmune diseases like multiple sclerosis, asthma, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, allergic airway inflammation, granulomatous lung disease, interstitial lung disease, allograft rejection, acute transplant rejection, inflammatory bowl disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, graft vs. host reaction, cancer chemotherapy, pathogenesis of multiple myeloma-associated bone destruction disease, angiogenesis, and HIV-1 infection specifically AIDS.
  • diseases selected from the group consisting of inflammation, chronic and acute inflammation, gout, acute pseudo
  • Figure 1 shows the inhibitory effect of sempervirine (Compound 1, CTCM111) on the binding of MlP-lalpha to CCR-1, CCR-4, and CCR-5 receptors using THP-1 cells.
  • Figure 2 shows inhibition effect of sempervirine (Compound 1, CTCM111) on
  • the compounds of the invention may have a chemokine receptor binding affinity (IC 50 ) below 500 uM, below 100 uM, below 500 nM, below 100 nM, below 50 nM, below 10 nM or below 1 nM; and may have a selective affinity for a selected chemokine receptor, such as a 10-fold selective affinity, a 50-fold selective affinity or a 100-fold selective affinity, for a selected chemokine receptor relative to an alternative chemokine receptor.
  • IC 50 chemokine receptor binding affinity
  • the compounds may have a binding affinity for CCR-1, CCR-4 or CCR-5 of below 500 uM, below 100 uM, below 100 nM, below 50 nM, below 10 nM or below 1 nM.
  • Receptor binding affinities may by assayed by any of a number of standard methods, such as competitive displacement of radioactively labeled ligands.
  • the invention relates to compounds having alternative substitutions and substituent groups, designated in formulae herein as "R", typically with a numeric subscript to identify the substituent group.
  • a substituent group is generally a group that replaces one or more hydrogen atoms attached to a parent structure.
  • Organic substituent groups are for example identified in the Handbook of Chemistry and Physics, 79th Edition, CRC Press (all of which are hereby incorporated by reference).
  • Substituent groups of the invention may for example be selected from groups having from 1 to 100 atoms, such as groups having 100 or fewer, 50 or fewer, 25 or fewer, 20 or fewer, 15 or fewer, 10 or fewer, 5 or fewer, 4, 3, 2, or 1 atom(s).
  • Atoms in such substituents may for example be selected from the group consisting of carbon, hydrogen, oxygen, nitrogen, halogen, sulfur, silicon, arsenic, boron, selenium and phosphorus.
  • Substituent groups may for example be substituted or unsubstitued alkyls, such as, Ci-io alkyls, C 1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C 1-10 cycloalkyls, C 3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C 1-10 alkenyls, C 2-6 alkenyls; substituted or unsubstitued alkynyls, such as C 1-10 alkynyls, C 2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyl
  • a substituent group may comprise a cyclic, heterocyclic or polycyclic group.
  • the term "cyclic group”, as used herein, includes cyclic saturated or unsaturated (optionally aromatic) group having from 3 to 10, 4 to 8, or 5 to 7 carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cyclic groups may be unsubstituted or substituted at one or more ring positions.
  • a cyclic group may for example be substituted with halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, heterocycles, hydroxyls, alkyloxyls, esters, aminos, nitros, thiols, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, sulfonates, selenoethers, ketones, aldehydes, esters, - CF 3 , -CN or can be alkaloid in nature forming dimers.
  • heterocyclic group includes cyclic saturated, unsaturated and aromatic groups having from 3 to 10, 4 to 8, or 5 to 7 carbon atoms, wherein the ring structure includes about one or more heteroatoms.
  • Heterocyclic groups may include pyrrolidine, oxolane, thiolane, indole, quinoline, imidazole, oxazole, pyridine, piperidine, piperazine, morpholine.
  • the heterocyclic ring may be substituted at one or more positions with such substituents as, for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, other heterocycles, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, -CF 3 , -CN.
  • Heterocycles may also be bridged or fused to other cyclic groups as described below.
  • polycyclic group as used herein is intended to refer to two or more saturated, unsaturated or aromatic cyclic rings in which two or more carbons are common to two adjoining rings, so that the rings are “fused rings". Rings that are joined through non-adjacent atoms may be termed "bridged" rings.
  • Each of the rings of the polycyclic group may be substituted with such substituents as described above, as for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, -CF 3 , or -CN.
  • substituents as described above, as for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls
  • alkyl refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 20 or fewer carbon atoms in its backbone (C 1 -C 20 for straight chain, C 3 -C 20 for branched chain), or 10 or fewer carbon atoms.
  • cycloalkyls may have from 4-10 carbon atoms in their ring structure, such as 5, 6 or 7 carbon rings.
  • lower alkyl as used herein means an alkyl group, as defined above, having from one to ten carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have chain lengths often or less carbons.
  • alkyl (or “lower alkyl) as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl groups), and esters (including alkyloxycarbonyl and aryloxycarbonyl groups)), thiocarbonyl, acyloxy, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, acylamino, amido, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.
  • carbonyl such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl groups), and esters (including alkyloxycarbonyl and aryloxycarbonyl groups)
  • the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
  • the substituents of a substituted alkyl may include substituted and unsubstituted forms of aminos, azidos, iminos, amidos, phosphoryls (including phosphonates and phosphinates), sulfonyls (including sulfates, sulfonamidos, sulfamoyls and sulfonates), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF 3 , -CN and the like. Exemplary substituted alkyls are described below.
  • Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF 3 , -CN, and the like.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aralkyl refers to an alkyl or alkylenyl group substituted with at least one aryl group. Exemplary aralkyls include benzyl (i.e., phenylmethyl), 2- naphthylethyl, 2-(2-pyridyl)propyl, 5-dibenzosuberyl, and the like.
  • alkylcarbonyl refers to -C(O)-alkyl.
  • arylcarbonyl refers to -C(O)-aryl.
  • alkyloxycarbonyl refers to the group -C(O)-O-alkyl, and the term “aryloxycarbonyl” refers to -C(O)-O-aryl.
  • acyloxy refers to -O-C(O)-R 8 , in which R 8 is alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl.
  • amino refers to -N(R ⁇ )(R ⁇ ), in which R ⁇ and R ⁇ are each independently hydrogen, alkyl, alkyenyl, alkynyl, aralkyl, aryl, or in which R ⁇ and R ⁇ together with the nitrogen atom to which they are attached form a ring having 4-8 atoms.
  • amino includes unsubstituted, monosubstituted (e.g., monoalkylamino or monoarylamino), and disubstituted (e.g., dialkylamino or alkylarylamino) amino groups.
  • acylamino refers to -N(R' 9 )C(O)-R 8 , in which R 8 is as defined above and R' is alkyl.
  • nitro means -NO 2 ;
  • halogen designates -F, - Cl, -Br or -I;
  • sulfhydryl means -SH; and
  • hydroxyl means -OH.
  • aryl as used herein includes 5-, 6- and 7-membered aromatic groups that may include from zero to four heteroatoms in the ring, for example, phenyl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazole, thiazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles" or "heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • Aryl groups can also be part of a polycyclic group.
  • aryl groups include fused aromatic moieties such as naphthyl, anthracenyl, quinolyl, indolyl, and the like.
  • the compounds of the invention may be used therapeutically in formulations or medicaments, such as for treatment of CCR-1, CCR-4 and CCR-5 mediated diseases.
  • the invention provides methods of medical treatment, in which a therapeutic dose of a compound of the invention is administered in a pharmacologically acceptable formulation.
  • the invention also provides therapeutic compositions comprising compounds of the invention and a pharmacologically acceptable excipient or carrier.
  • the therapeutic composition may be soluble in an aqueous solution at a physiologically acceptable pH.
  • the invention provides pharmaceutical compositions (medicaments) containing
  • compositions may include compounds of the invention in an effective amount, meaning a therapeutically or prophylactically effective amount, sufficient to modulate CCR-1, CCR-4 and CCR-5 activity, and a pharmaceutically acceptable carrier.
  • the compositions of the invention may include compound of the invention in a therapeutically or prophylactically effective amount sufficient to modulate the activity of MIP-1 alpha, and a pharmaceutically acceptable carrier.
  • Compounds of the invention may also be used in combination with other compositions and procedures for the treatment of diseases.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as modulation of CCR-1, CCR-4, CCR-5 or MIP-1 alpha activity.
  • a therapeutically effective amount of a compound of the invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of compounds of the invention to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • a prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as modulation of CCR-1, CCR-4, CCR-5 or MIP-1 alpha activity.
  • a prophylactically effective amount can be determined as described above for the therapeutically effective amount. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • a preferred range for therapeutically or prophylactically effective amounts of compounds of the invention may be 0.1 nM-0.1 M, 0.1 nM-0.05 M, 0.05 nM-15 ⁇ M or 0.01 nM-10 ⁇ M.
  • total daily dose may range from about 0.001 to about lmg/kg of patients body mass. Dosage values may vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the methods of the invention.
  • the amount of a compound of the invention in a therapeutic composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for parenteral administration.
  • the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin.
  • compounds of the invention can be administered in a time release formulation, for example in a composition which includes a slow release polymer.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
  • Sterile injectable solutions can be prepared by incorporating compounds of the invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • compounds of the invention may be formulated with one or more additional compounds that enhance the solubility of compounds of the invention.
  • Pharmaceutically acceptable salts include salts that are well known to those skilled in the art such as halogen or nitrite salts and basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, alicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable cation salts may include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
  • compositions of the present invention comprising compounds of the invention, may be provided in containers having labels that provide instructions for use of compounds of the invention to treat a disease, such as a chemokine or chemokine receptor mediated diseases.
  • Such diseases may for example include inflammation, acute inflammation, chronic inflammation, psoriasis, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, autoimmune diseases like multiple sclerosis, allograft rejection, chronic transplant rejection, asthma, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis, focal ischemia, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease. Crohn's disease, graft vs. host reaction, restinosis, angiogenesis, fungal diseases, HIV-infection, specifically AIDS.
  • autoimmune diseases like multiple sclerosis, allograft rejection, chronic transplant rejection, asthma, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis, focal ischemia, atopic
  • Semperverine (2,3,4, 13-Tetrahydro-lH-benz[g]indolo[2,3- ⁇ ]quinolizin-6-ium) (CAS Registry No. 6882-99-1) or 3,4,5,6,14,15,20,21- Octadehydroyohimbanium) (a pentacyclic anhydronium indole alkaloid from Gelsemium sempervirens, disclosed herein may be prepared in a variety of ways known to those skilled in the art.
  • a general procedure for preparing semperverine is as follows:
  • the pentacyclic anhydronium indole alkaloid of Gelsemium semperviren may be synthesized in four steps starting from [4.3.0]non-8-one (d) which may be turned into hexahydroisocl roman-3-one (e) by Baeyer-Villiger oxidation. Refluxing e with tryptamine in ethanol may afford N-2-(3-indolyl)-ethyl-2-(hydroxymethyl)-hexa- hydrophenylacetamide (g).
  • Compound g may yield compound h via double cyclizations using freshly distilled phosphoryl chloride which on dehydrogenation with 2,3-dichloro- 5,6-dicyanobenzoquinone in presence of glacial acetic acid under N atmosphere may afford semperverine (1).
  • FIG. 1 illustrates results of the binding studies conducted using 125 I labeled MIP-1 alpha as competitor and THP-1 cell line expressing CCR-1, CCR-4 and CCR-5 receptors.
  • CTCMl l l was added at the
  • THP-1 cells were assessed for I-MIP-lalpha binding. The results are expressed as percentages of the maximum specific binding that was determined without CTCM.l l l, and represent the mean +/- one S .D .

Abstract

In various aspects, the invention relates to compounds capable of binding to the macrophage inflammatory protein - one alpha (MIP-1alpha) receptors CCR-1, CCR-4, and CCR-5. In various embodiment, the invention provides methods for the use of such compounds in the modulation of processes mediated by such receptors, including in the treatment of diseases, such as diseases mediated by MIP-1alpha, CCR-1, CCR-4 or CCR-5. Pharmaceutical compositions of the compounds of the invention are accordingly provided in alternative aspects of the invention. Compounds of the invention may for example have the following Formula (CTCM111):

Description

MIP-1 ALPHA RECEPTOR LIGANDS - DRUGS FOR T-CELL MEDIATED AND
AUTOIMMUNE DISEASES
FIELD OF THE INVENTION This invention relates to therapeutic organic compounds and uses thereof, including the treatment of MIP-1 alpha receptor mediated diseases.
BACKGROUND OF THE INVENTION
Chemokines are a diverse group of small secreted basic proteins, that regulate the chemotactic migration and activation of a number of different leukocytes, particularly in the context of activation of the immune response during inflammatory conditions.
Examples of cells that have been shown to chemotactically respond to and become activated by chemokines include a variety of leukocytes, such as neutrophils, eosinophils, basophils, monocytes, macrophages, as well as B lymphocytes and different types of T lymphocytes.
Based on the structural similarity, chemokines may be subdivided into four subfamilies, CXC, CC, C and CX3C, depending on the position of the first two cysteine residues. At least 16 chemokine receptors, including nine CC-chemokine receptors and five CXC-chemokine receptors, have been identified.
The CC chemokine family includes macrophage inflammatory protein (MIP) - 1 alpha, MlP-lbeta, RANTES (regulated on activation normal T-cell expressed and secreted), monocyte chemotactic protein (MCP)-l, -2, -3, and —4. The CC chemokines are generally chemotactic for T cells, monocytes, basophils, and eosinophils, but not neutrophils. These chemokmes are thought to attract leukocytes by binding to the seven transmembrane-spanning G-protein coupled receptors CCR-1 through CCR-8. CC chemokine receptors that have been cloned include: CC chemokine receptor-1 (CCR-1), which recognizes MIP-1 alpha and RANTES, CCR-2 which recognizes MCP-1; CCR-3 which recognizes eotoxin; CCR-4, which recognizes MIP-1 alpha, RANTES and MCP-1; and CCR-5, which recognizes MlP-lalpha, MlP-lbeta, and RANTES. Chemokines, and chemokine receptors, are thought to mediate (i.e. play a role in) a variety of disease states, including the pathogenesis of chronic inflammatory diseases, such as multiple sclerosis (MS) and rheumatoid arthritis (RA). For example, expression of RANTES and MIP-1 alpha has been correlated with disease onset in the mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. It has been demonstrated that antibodies to MIP-1 alpha prevent the development of both acute and relapsing paralytic disease in EAE, as well as infiltration of mononuclear cells into the central nervous system; treatment with MIP-1 alpha antibody was also able to ameliorate the severity of ongoing clinical EAE disease. These results indicate that MIP-1 alpha may play a role in the pathology of T-cell mediated autoimmune diseases such as EAE. MIP- 1 alpha is reportedly elevated in chronic interstitial lung disease and also exerts a prominent effect on the persistent recruitment of mononuclear cells into the inflamed lung. It has also been suggested that MIP-1 alpha is not only important in monocyte recruitment during Thl type inflammatory lesion development, but also has a role in eosinophil recruitment during a Th2 type allergic airway response. Evidence such as this regarding the physiological role of MIP-1 alpha suggests that a compound that inhibit MIP-1 alpha receptor/ligand interaction may be useful in the treatment of T-cell mediated diseases, including autoimmune diseases, inflammation, multiple sclerosis, chronic interstitial lung disease, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, allergy, contact hypersensitivity, psoriasis, systemic lupus erythematosus, and diseases mediated by superantigen toxins such as staphylococcal enterotoxin B, and toxic shock syndrome toxin 1.
The severe bone destruction commonly associated with multiple myeloma (MM) is reportedly due to increased osteoclast (OC) activity induced by as yet unidentified factor(s) produced by the MM cells. It's been reported that MIP-1 alpha, is produced by MM cells and that its levels are elevated in bone marrow plasma of MM patients compared with other hematological malignancies and normal controls. It has been shown that MIP- 1 alpha increases OC formation and bone resorption in vivo when expressed adjacent to bone surfaces. Evidence such as this has led to the suggestion that MlP-lalpha plays an important role in bone destruction, such as the pathogenesis of MM. MIP-1 alpha, as well as other chemokines, has been shown to inhibit T-cell infection by the human immunodeficiency virus (HIV), the agent responsible for causing human Acquired Immune Deficiency Syndrome (AIDS). In particular, RANTES, MIP- 1 alpha, and MIP-1 beta have shown a dose-dependent ability to inhibit specific strains of HIV from infecting cultured T-cell lines.
The chemokine receptor CCR-5 reportedly binds MIP-1 alpha, MIP-1 beta, and RANTES, and constitutes a major co-receptor allowing infection of CD4+ T lymphocytes, macrophages, and microglial cells by macrophage-tropic strains of human and simian immunodeficiency virus. A synthetic truncated CCR-5 molecule that was capable of ligand binding but not of transducing signals by means of Ca2+ flux or chemotaxis, has been shown to inhibit CCR-5 dependent HIV infection, suggesting that CCR-5 ligands may inhibit HIV infection.
A wide variety of organic compounds that are found to be chemokine receptor ligands have been suggested to have therapeutic activity in diverse chemokine mediated diseases, including pyrrolidines, piperidines, cyclic amines, spiro-substituted azacycles and substituted aminoquinolines (see U.S. Patent Nos. 6,204,294; 6,166,037; 6,140,349; 6,136,827; 6,124,319; 6,013,644; 5,962,462; and 5,919,776). Sempervirine is a pentacyclic anhydronium indole alkaloid (2,3,4,13-tetrahydro-lH-benzo[g]indolo[2,3-a]quinolizin-6- ium; CAS Registry No. 6882-99-1; or 3,4,5,6,14,15,20,21-octadehydroyohimbanium; C1 H16N2, molecular weight: 272.35). None of the above patents reported the use of 3 A5,6 4,15,20,21-octadehydrovohimbanium in the treatment of chemokine mediated diseases.
Figure imgf000005_0001
Compound 1: sempervirine (also identified herein as CTCM111)
Sempervirine may be isolated from Gelsemium sempervirens (Loganiaceae) Ait. F., (Carolina jessamine) commonly known as yellow jessamine. Sempervirine, which is a quinolizin derivative in the beta-carboline class of alkaloids, may also be prepared using a variety of known synthetic approaches.
SUMMARY OF THE INVENTION
In various aspects, the invention relates to compounds capable of binding to the macrophage inflammatory protein - one alpha (MIP-1 alpha) receptors CCR-1, CCR-4, and CCR-5. In various embodiment, the invention provides methods for the use of such compounds in the modulation of processes mediated by such receptors, including in the treatment of diseases, such as diseases mediated by MIP-1 alpha, CCR-1, CCR-4 or CCR- 5. Pharmaceutical compositions of the compounds of the invention are accordingly provided in alternative aspects of the invention.
In some embodiments, the invention relates to methods of using pentacyclic compounds of formula (I), (II), (III), (IV), (V) or (VI), or pharmaceutically acceptable salts thereof, to treat, or to formulate a medicament for the treatment of, a chemokine mediated disease state:
(Formula I) e.g., anhydroalstonatine
Figure imgf000006_0001
(Formula II) e.g., sempervirine and its salt (wherein X represents a counterion of the salf of the compound, and H is 0 or an integer enumerating the counterion).
Figure imgf000006_0002
(Formula III) e.g.,
Figure imgf000007_0001
(Formula IV) e.g., Alastonine, ajmalicine, δ-yohimbine
Figure imgf000007_0002
(Formula V) e.g., anhydroalastonine, yohimbine HCl, Raunescine, Yohimbinic acid monohydrate
Figure imgf000007_0003
(Formula VI) e.g., Flavopereirine, dehydrogeissoschizine, isositsirikme, geissospermine
Figure imgf000007_0004
In the foregoing formulae:
"a" may be 0 or an integer from 1 to 4; "b" may be 0 or an integer from 1 to 8;
"c" may be 0 or an integer from 1 to 2
"d" may be 0 or an integer from 1 to 2
"X" is a counterion, and may for example be Cl", Br", T or NO3 ". Where "a", "b", "c" or "d" are greater than 1, the relevant substituents need not be the same, so that for example if a-2 in the substituent (R 2, the two Rl groups may be the same or different.
In alternative embodiments, ring A may be aromatic or aliphatic. Rings B, C and D are hetrocyclic with 'N' substituents, as shown. Ring C and D may be aromatic or aliphatic or in other words, anhydro or dehydro at one or more 'C positions in the ring. Ring E may be aliphatic or aromatic, with or with out hetero-atom substitutions. Where a ring has more than one site for attachment of substitutents, the substituent thereon may be a cyclic substituent that attaches to the ring at more than one position.
In alternative embodiments, R\ and R2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstituted heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; - CN; and combinations thereof.
In alternative embodiments, R3, R4, R5, R6j R ; R8, R9; R10> and R11, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent may be selected from the group consisting of: H; substituted or unsubstitued alkyls, such as CMO alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; alcohols; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; or dimeric form of parent compound and combinations thereof.
In some embodiments, compounds of the invention may be used to treat diseases mediated by a chemokine or a chemokine receptor. The chemokine may for example be selected from the group consisting of: MIP-1 alpha, and chemokines that bind to a chemokine receptor in a mammal selected from the group such as CCR-1, CCR-4 and CCR-5. The chemokine receptor may be selected from the group consisting of CCR-1, CCR-4 and CCR-5
In various embodiments, the invention provides for the use of compounds of the invention in the treatment of diseases selected from the group consisting of inflammation, chronic and acute inflammation, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthrifis, autoimmune diseases like multiple sclerosis, asthma, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, allergic airway inflammation, granulomatous lung disease, interstitial lung disease, allograft rejection, acute transplant rejection, inflammatory bowl disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, graft vs. host reaction, cancer chemotherapy, pathogenesis of multiple myeloma-associated bone destruction disease, angiogenesis, and HIV-1 infection specifically AIDS.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the inhibitory effect of sempervirine (Compound 1, CTCM111) on the binding of MlP-lalpha to CCR-1, CCR-4, and CCR-5 receptors using THP-1 cells.
Figure 2 shows inhibition effect of sempervirine (Compound 1, CTCM111) on
MlP-lalpha induced [Ca+2]; mobilization in THP-1 cells. DETAILED DESCRIPTION OF THE INVENTION
In some embodiments, the compounds of the invention may have a chemokine receptor binding affinity (IC50) below 500 uM, below 100 uM, below 500 nM, below 100 nM, below 50 nM, below 10 nM or below 1 nM; and may have a selective affinity for a selected chemokine receptor, such as a 10-fold selective affinity, a 50-fold selective affinity or a 100-fold selective affinity, for a selected chemokine receptor relative to an alternative chemokine receptor. For example, in some embodiments, the compounds may have a binding affinity for CCR-1, CCR-4 or CCR-5 of below 500 uM, below 100 uM, below 100 nM, below 50 nM, below 10 nM or below 1 nM. Receptor binding affinities may by assayed by any of a number of standard methods, such as competitive displacement of radioactively labeled ligands.
In various aspects, the invention relates to compounds having alternative substitutions and substituent groups, designated in formulae herein as "R", typically with a numeric subscript to identify the substituent group. A substituent group is generally a group that replaces one or more hydrogen atoms attached to a parent structure. Organic substituent groups are for example identified in the Handbook of Chemistry and Physics, 79th Edition, CRC Press (all of which are hereby incorporated by reference). Substituent groups of the invention may for example be selected from groups having from 1 to 100 atoms, such as groups having 100 or fewer, 50 or fewer, 25 or fewer, 20 or fewer, 15 or fewer, 10 or fewer, 5 or fewer, 4, 3, 2, or 1 atom(s). Atoms in such substituents may for example be selected from the group consisting of carbon, hydrogen, oxygen, nitrogen, halogen, sulfur, silicon, arsenic, boron, selenium and phosphorus.
Substituent groups may for example be substituted or unsubstitued alkyls, such as, Ci-io alkyls, C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C1-10 cycloalkyls, C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C1-10 alkenyls, C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C1-10 alkynyls, C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; esters; -CF3; -CN; and combinations thereof. Substituent groups which are themselves substituted may be substituted with the similar substituents. In some embodiments, a substituent group may comprise a cyclic, heterocyclic or polycyclic group. The term "cyclic group", as used herein, includes cyclic saturated or unsaturated (optionally aromatic) group having from 3 to 10, 4 to 8, or 5 to 7 carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cyclic groups may be unsubstituted or substituted at one or more ring positions. A cyclic group may for example be substituted with halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, heterocycles, hydroxyls, alkyloxyls, esters, aminos, nitros, thiols, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, sulfonates, selenoethers, ketones, aldehydes, esters, - CF3, -CN or can be alkaloid in nature forming dimers.
The term "heterocyclic group" includes cyclic saturated, unsaturated and aromatic groups having from 3 to 10, 4 to 8, or 5 to 7 carbon atoms, wherein the ring structure includes about one or more heteroatoms. Heterocyclic groups may include pyrrolidine, oxolane, thiolane, indole, quinoline, imidazole, oxazole, pyridine, piperidine, piperazine, morpholine. The heterocyclic ring may be substituted at one or more positions with such substituents as, for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, other heterocycles, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, -CF3, -CN. Heterocycles may also be bridged or fused to other cyclic groups as described below.
The term "polycyclic group" as used herein is intended to refer to two or more saturated, unsaturated or aromatic cyclic rings in which two or more carbons are common to two adjoining rings, so that the rings are "fused rings". Rings that are joined through non-adjacent atoms may be termed "bridged" rings. Each of the rings of the polycyclic group may be substituted with such substituents as described above, as for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, -CF3, or -CN. The term "alkyl" refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In some embodiments, a straight chain or branched chain alkyl has 20 or fewer carbon atoms in its backbone (C1-C20 for straight chain, C3-C20 for branched chain), or 10 or fewer carbon atoms. In some embodiments, cycloalkyls may have from 4-10 carbon atoms in their ring structure, such as 5, 6 or 7 carbon rings. Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, having from one to ten carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have chain lengths often or less carbons.
The term "alkyl" (or "lower alkyl") as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, ketones (including alkylcarbonyl and arylcarbonyl groups), and esters (including alkyloxycarbonyl and aryloxycarbonyl groups)), thiocarbonyl, acyloxy, alkoxyl, phosphoryl, phosphonate, phosphinate, amino, acylamino, amido, amidine, imino, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. The moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of aminos, azidos, iminos, amidos, phosphoryls (including phosphonates and phosphinates), sulfonyls (including sulfates, sulfonamidos, sulfamoyls and sulfonates), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.
The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. The term "aralkyl", as used herein, refers to an alkyl or alkylenyl group substituted with at least one aryl group. Exemplary aralkyls include benzyl (i.e., phenylmethyl), 2- naphthylethyl, 2-(2-pyridyl)propyl, 5-dibenzosuberyl, and the like.
The term "alkylcarbonyl", as used herein, refers to -C(O)-alkyl. Similarly, the term "arylcarbonyl" refers to -C(O)-aryl. The term "alkyloxycarbonyl", as used herein, refers to the group -C(O)-O-alkyl, and the term "aryloxycarbonyl" refers to -C(O)-O-aryl. The term "acyloxy" refers to -O-C(O)-R8, in which R8 is alkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclyl.
The term "amino", as used herein, refers to -N(Rα)(Rβ), in which Rα and Rβ are each independently hydrogen, alkyl, alkyenyl, alkynyl, aralkyl, aryl, or in which Rα and Rβ together with the nitrogen atom to which they are attached form a ring having 4-8 atoms. Thus, the term "amino", as used herein, includes unsubstituted, monosubstituted (e.g., monoalkylamino or monoarylamino), and disubstituted (e.g., dialkylamino or alkylarylamino) amino groups. The term "amido" refers to -C(O)-N(R )(R10), in which R9 and R10 are as defined above. The term "acylamino" refers to -N(R'9)C(O)-R8, in which R8 is as defined above and R' is alkyl.
As used herein, the term "nitro" means -NO2 ; the term "halogen" designates -F, - Cl, -Br or -I; the term "sulfhydryl" means -SH; and the term "hydroxyl" means -OH.
The term "aryl" as used herein includes 5-, 6- and 7-membered aromatic groups that may include from zero to four heteroatoms in the ring, for example, phenyl, pyrrolyl, furyl, thiophenyl, imidazolyl, oxazole, thiazolyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like. Aryl groups can also be part of a polycyclic group. For example, aryl groups include fused aromatic moieties such as naphthyl, anthracenyl, quinolyl, indolyl, and the like.
The following are examples of compounds coming within one or more of formulae (I) to (VI), which compounds may be synthesized or isolated from plants, bearing an anhydronium indole moiety (an indolo-quinolizine moiety). These examples are merely illustrative of alternative embodiments and are not exhaustive nor do the examples limit the scope of the invention.
1. Anhydroalstonatine from Alstonia venenata
Figure imgf000014_0001
2. Alastonatine or Raubasine from Rauwolfia serpentina
Figure imgf000014_0002
3. Raunescine from Rauwolfia canescens
Figure imgf000014_0003
4. Yohimbinic acid monohydrate
Figure imgf000014_0004
5. 4,21 -dehydrogeissoschizine from Guettarda eximia
Figure imgf000015_0001
6. Dihydrocorynantheol from Aspidosperma marcgravianum
Figure imgf000015_0002
7. Isositsirikme from Guettarda eximia
Figure imgf000015_0003
8. Flavopereirine
Figure imgf000015_0004
9. Geissospermine from Geissospermum vellosii
Figure imgf000015_0005
In various embodiments, the compounds of the invention may be used therapeutically in formulations or medicaments, such as for treatment of CCR-1, CCR-4 and CCR-5 mediated diseases. The invention provides methods of medical treatment, in which a therapeutic dose of a compound of the invention is administered in a pharmacologically acceptable formulation. Accordingly, the invention also provides therapeutic compositions comprising compounds of the invention and a pharmacologically acceptable excipient or carrier. The therapeutic composition may be soluble in an aqueous solution at a physiologically acceptable pH.
The invention provides pharmaceutical compositions (medicaments) containing
(comprising) compound of the invention. Such compositions may include compounds of the invention in an effective amount, meaning a therapeutically or prophylactically effective amount, sufficient to modulate CCR-1, CCR-4 and CCR-5 activity, and a pharmaceutically acceptable carrier. In other embodiments, the compositions of the invention may include compound of the invention in a therapeutically or prophylactically effective amount sufficient to modulate the activity of MIP-1 alpha, and a pharmaceutically acceptable carrier. Compounds of the invention may also be used in combination with other compositions and procedures for the treatment of diseases.
A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as modulation of CCR-1, CCR-4, CCR-5 or MIP-1 alpha activity. A therapeutically effective amount of a compound of the invention may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of compounds of the invention to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as modulation of CCR-1, CCR-4, CCR-5 or MIP-1 alpha activity. A prophylactically effective amount can be determined as described above for the therapeutically effective amount. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
In particular embodiments, a preferred range for therapeutically or prophylactically effective amounts of compounds of the invention may be 0.1 nM-0.1 M, 0.1 nM-0.05 M, 0.05 nM-15 μM or 0.01 nM-10 μM. Alternatively, total daily dose may range from about 0.001 to about lmg/kg of patients body mass. Dosage values may vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the methods of the invention.
The amount of a compound of the invention in a therapeutic composition may vary according to factors such as the disease state, age, sex, and weight of the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
As used herein "pharmaceutically acceptable carrier" or "excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. In one embodiment, the carrier is suitable for parenteral administration. Alternatively, the carrier can be suitable for intravenous, intraperitoneal, intramuscular, sublingual or oral administration. Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, monostearate salts and gelatin. Moreover, compounds of the invention can be administered in a time release formulation, for example in a composition which includes a slow release polymer. The active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers (PLG). Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
Sterile injectable solutions can be prepared by incorporating compounds of the invention in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. In accordance with an alternative aspect of the invention, compounds of the invention may be formulated with one or more additional compounds that enhance the solubility of compounds of the invention.
Pharmaceutically acceptable salts include salts that are well known to those skilled in the art such as halogen or nitrite salts and basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, alicylic acid, phenylacetic acid and mandelic acid. In alternative embodiments, pharmaceutically acceptable cation salts may include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
In accordance with another aspect of the invention, therapeutic compositions of the present invention, comprising compounds of the invention, may be provided in containers having labels that provide instructions for use of compounds of the invention to treat a disease, such as a chemokine or chemokine receptor mediated diseases. Such diseases may for example include inflammation, acute inflammation, chronic inflammation, psoriasis, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, autoimmune diseases like multiple sclerosis, allograft rejection, chronic transplant rejection, asthma, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis, focal ischemia, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease. Crohn's disease, graft vs. host reaction, restinosis, angiogenesis, fungal diseases, HIV-infection, specifically AIDS.
EXAMPLES
The following examples are illustrative only of various aspects of the invention.
Isolation of "Semperverine":
Sempervirine [2,3,4, 13 -Tetrahydro- 1 H-benz[g]indolo [,3-a]quinolizin-6-ium Sempervine] (1), a beta-Carboline class of natural pentacyclic anhydronium indole alkaloid may be isolated from Gelsemium sempervirens Ait. F. (Loganiaceae) by a variety of ways known to those skilled in the art.
Synthesis of Compound 1:
The uses of Semperverine (2,3,4, 13-Tetrahydro-lH-benz[g]indolo[2,3- α]quinolizin-6-ium) (CAS Registry No. 6882-99-1) or 3,4,5,6,14,15,20,21- Octadehydroyohimbanium) (a pentacyclic anhydronium indole alkaloid from Gelsemium sempervirens, disclosed herein may be prepared in a variety of ways known to those skilled in the art.
A general procedure for preparing semperverine is as follows:
Ba(QH)2
Figure imgf000020_0001
a
Figure imgf000020_0002
Compound 1
Figure imgf000020_0003
The pentacyclic anhydronium indole alkaloid of Gelsemium semperviren may be synthesized in four steps starting from [4.3.0]non-8-one (d) which may be turned into hexahydroisocl roman-3-one (e) by Baeyer-Villiger oxidation. Refluxing e with tryptamine in ethanol may afford N-2-(3-indolyl)-ethyl-2-(hydroxymethyl)-hexa- hydrophenylacetamide (g). Compound g may yield compound h via double cyclizations using freshly distilled phosphoryl chloride which on dehydrogenation with 2,3-dichloro- 5,6-dicyanobenzoquinone in presence of glacial acetic acid under N atmosphere may afford semperverine (1). Receptor Binding
This example discloses the ability of sempervirine to inhibit binding of MIP-1 alpha to the MIP-1 alpha receptors (CCR-1, CCR-4 and CCR-5). Figure 1 illustrates results of the binding studies conducted using 125I labeled MIP-1 alpha as competitor and THP-1 cell line expressing CCR-1, CCR-4 and CCR-5 receptors. CTCMl l l was added at the
125 concentrations illustrated in the presence of 4nM I-MIP-lalpha. THP-1 cells were assessed for I-MIP-lalpha binding. The results are expressed as percentages of the maximum specific binding that was determined without CTCM.l l l, and represent the mean +/- one S .D .
Calcium Release
A rapid, transient rise in the free cytosolic Ca2+ concentration ([Ca2+];) is one of the events in neutrophil activation and is thought to be involved in many cellular processes. Both Ca2+ release from intracellular stores and Ca2+ influx from the extracellular space may contribute to the rise in [Ca2+]i. Figure 2 shows the inhibition of MIP-1 alpha-induced
2+
[Ca ]; mobilization by sempervirine (Compound 1; CTCMl 11) in a human monocyte cell line (THP-1 cells; available for example from the American Type Culture Collection, Tumor Immunology Bank #202, Rockville, Md., accession no. ATCC TIB 202). Fura- 2, AM loaded THP-1 cells were incubated with CTCMl 11 for 60 min prior to induction of [Ca2+]j mobilization by lOnM MIP-1 alpha. Result indicate the physiological effect of sempervirine (1) on MIP-1 alpha-induced Ca2+ concentration. Compound 1 showed an
2+ inhibition of MIP-1 alpha-induced [Ca ]; mobilization in THP-1 cells at the concentration of 5 uM.
Conclusion
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. In the specification, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. Citation of references herein shall not be construed as an admission that such references are prior art to the present invention. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

WHAT IS CLAIMED IS:
1. The use of an effective amount of a compound of formula (I), (II), (III),
(IV), (V), or (VI) or a pharmaceutically acceptable salt thereof, to formulate a medicament for the treatment of a chemokine mediated disease state, or a disease state mediated by a receptor of the chemokine: (Formula I)
Figure imgf000023_0001
(Formula II)
Figure imgf000023_0002
(Formula III)
Figure imgf000023_0003
(Formula IV)
Figure imgf000024_0001
(Formula V)
Figure imgf000024_0002
(Formula VI)
Figure imgf000024_0003
wherein:
"a" is 0 or an integer from 1 to 4;
"b" is 0 or an integer from 1 to 8;
"c" is 0, 1 or 2;
"d" is 0, 1 or 2;
"H" is 0 or an integer;
"X" is a counterion;
Ri and R at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof; R3, R^ R5, R6; R > R8; R j R10; Rπ and R12, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-10 alkyls; substituted or unsubstitued cycloalkyls, such as C3- cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof; and, wherein the chemokine is selected from the group consisting of: MIP- 1 alpha, and chemokines that bind to CCR-1, CCR-4 or CCR-5; and the receptor of the chemokine is selected from the group consisting of CCR-1, CCR-4 and CCR-5.
2. The use of an effective amount of a compound of formula (I), (II), (III),
(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, to treat a chemokine mediated disease state, or a disease state mediated by a receptor of the chemokine:
(Formula I)
Figure imgf000026_0001
(Formula II)
Figure imgf000026_0002
(Formula III)
Figure imgf000026_0003
(Formula IV)
Figure imgf000026_0004
(Formula V)
Figure imgf000027_0001
(Formula VI)
Figure imgf000027_0002
wherein:
"a" is 0 or an integer from 1 to 4;
"b" is 0 or an integer from 1 to 8;
"c" is 0, 1 or 2;
"d" is 0, 1 or 2;
"H" is 0 or an integer;
"X" is a counterion;
R1 and R2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C -6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof;
R3, R^ R5, R6j R ; R ; R9; R10; Rπ and R12, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as Ci-io alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof; and, wherein the chemokine is selected from the group consisting of: MIP- 1 alpha, and chemokines that bind to CCR-1, CCR-4 or CCR-5; and the receptor of the chemokine is selected from the group consisting of CCR-1, CCR-4 and CCR-5.
3. A method of using a compound to treat a patient in need of such treatment, comprising administering to the patient an effective amount of the compound of formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof, wherein the patient is suffering from a chemokine mediated disease state, or a disease state mediated by a receptor of the chemokine: (Formula I)
Figure imgf000028_0001
(Formula II)
Figure imgf000029_0001
(Formula III)
Figure imgf000029_0002
(Formula IV)
Figure imgf000029_0003
(Formula V)
Figure imgf000029_0004
(Formula VI)
Figure imgf000030_0001
wherein: "a" is 0 or an integer from 1 to 4;
"b" is 0 or an integer from 1 to 8; "c" is 0, 1 or 2; "d" is 0, 1 or 2; "H" is 0 or an integer; "X" is a counterion;
Ri and R2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof;
R3, R4; R5, R6> R , R8, R9ι Rio, Rπ and R12, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-10 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; alkyloxyls; esters; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; alkyloxyls; esters; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -
CN; or can be alkaloid in nature forming dimmer and combinations thereof; and, wherein the chemokine is selected from the group consisting of: .MIP- 1 alpha, and chemokines that bind to CCR-1, CCR-4 or CCR-5; and the receptor of the chemokine is selected from the group consisting of CCR-1, CCR-4 and CCR-5. .
4. The use of a compound in accordance with claim 1, 2 or 3 wherein the compound binds to the chemokine receptor with a binding affinity below
100 nM.
5. The use of a compound in accordance with claim 1, 2, 3 or 4, wherein the disease state is selected from the group consisting of inflammation, chronic and acute inflammation, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, autoimmune diseases like multiple sclerosis, asthma, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, allergic airway inflammation, granulomatous lung disease, interstitial lung disease, allograft rejection, chronic transplant rejection, inflammatory bowl disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, graft vs. host reaction, pathogenesis of multiple myeloma-associated bone destruction disease, angiogenesis, HIV- 1 infection and AIDS.
6. The use of the compound in accordance with any one of claims 1 to 5, wherein the compound is sempervirine.
7. The use of the compound in accordance with any one of claims 1 to 5, wherein the compound has the following formula:
Figure imgf000032_0001
8. A method of using a compound to modulate a cellular process, comprising treating a cell with an effective amount of the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, wherein the cell has a chemokine receptor and the compound binds specifically to the chemokine receptor:
(Formula I)
Figure imgf000032_0002
(Formula II)
Figure imgf000032_0003
(Formula III)
Figure imgf000033_0001
(Formula IV)
Figure imgf000033_0002
(Formula V)
Figure imgf000033_0003
(Formula VI)
Figure imgf000033_0004
wherein:
"a" is 0 or an integer from 1 to 4;
"b" is 0 or an integer from 1 to 8;
"c" is 0, 1 or 2;
"d" is 0, 1 or 2; "H" is 0 or an integer; "X" is a counterion;
Ri and R2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof;
R3, R4; R5, R6; R7; R8j R9; R10, Rπ and R12, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-10 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; alkyloxyls; esters; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; or can be alkaloid in nature forming dimmer and combinations thereof; and, wherein the chemokine receptor is selected from the group consisting of
MIP-1 alpha receptors, CCR-1, CCR-4 and CCR-5.
9. The use of a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, as an active pharmaceutical substance, wherein the cell has a chemokine receptor and the compound binds specifically to the chemokine receptor:
(Formula I)
Figure imgf000035_0001
(Formula II)
Figure imgf000035_0002
(Formula III)
Figure imgf000035_0003
(Formula IV)
Figure imgf000036_0001
(Formula V)
Figure imgf000036_0002
(Formula VI)
Figure imgf000036_0003
wherein:
"a" is 0 or an integer from 1 to 4;
"b" is 0 or an integer from 1 to 8;
"c" is 0, 1 or 2;
"d" is 0, 1 or 2;
"H" is 0 or an integer;
"X" is a counterion;
Ri and R2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1- allcyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof; R3, Rt, R5, R6; R ; R8; R9] Rτo, Rπ and R12, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-10 alkyls; substituted or unsubstitued cycloalkyls, such as C -6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; alkyloxyls; esters; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; or can be alkaloid in nature forming dimmer and combinations thereof; and, wherein the chemokine receptor is selected from the group consisting of MlP-lalpha receptors, CCR-1, CCR-4 and CCR-5.
10. A pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent, wherein the compound binds specifically to a chemokine receptor:
(Formula I)
Figure imgf000038_0001
(Formula II)
Figure imgf000038_0002
(Formula III)
Figure imgf000038_0003
(Formula IV)
Figure imgf000038_0004
(Formula V)
Figure imgf000039_0001
(Formula VI)
Figure imgf000039_0002
wherein:
"a" is 0 or an integer from 1 to 4;
"b" is 0 or an integer from 1 to 8;
"c" is 0, 1 or 2;
"d" is 0, 1 or 2;
"H" is 0 or an integer;
"X" is a counterion;
Ri and R2 at each occurance may independently be selected from substituents having 30 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as C1-6 alkyls; substituted or unsubstitued cycloalkyls, such as C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2-6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; -CN; and combinations thereof; R3, R^ R5, R6; R7j R8, R , R10j Rπ and R12, at each occurance may independently be selected from substituents having 70 or fewer atoms, wherein the substituent is selected from the group consisting of: H; substituted or unsubstitued alkyls, such as Ci-io alkyls; substituted or unsubstitued cycloalkyls, such as
C3-6 cycloalkyls; substituted or unsubstitued alkenyls, such as C2-6 alkenyls; substituted or unsubstitued alkynyls, such as C2.6 alkynyls; substituted or unsubstitued aryls; substituted or unsubstitued heterocycles; hydroxyls; alkyloxyls; esters; aminos; nitros; thiols; primary, secondary or tertiary amines; imines; amides; phosphonates; phosphines; carbonyls; carboxyls; alkyloxyls; esters; silyls; epoxides; ethers; thioethers; sulfonyls; sulfonates; selenoethers; ketones; aldehydes; lactones; lactams; esters; -CF3; - CN; or can be alkaloid in nature forming dimmer and combinations thereof; and, wherein the chemokine receptor is selected from the group consisting of MlP-lalpha receptors, CCR-1, CCR-4 and CCR-5.
11. The method of claim 8 wherein the compound binds to the chemokine receptor with a binding affinity below 100 nM.
12. The method of claim 8 wherein the compound is sempervirine.
13. The method of claim 8, wherein the cellular process is monocyte activation and the cell is a monocyte.
14. The method of claim 8, wherein the process is inflammation and the cell is a leukocyte.
15. The invention substantially as hereinbefore described and with reference to the examples and drawings.
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