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WO1997016188A1 - Nouveaux inhibiteurs de peptides se liant aux proteines de type ii du cmh - Google Patents

Nouveaux inhibiteurs de peptides se liant aux proteines de type ii du cmh Download PDF

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Publication number
WO1997016188A1
WO1997016188A1 PCT/US1996/017134 US9617134W WO9716188A1 WO 1997016188 A1 WO1997016188 A1 WO 1997016188A1 US 9617134 W US9617134 W US 9617134W WO 9716188 A1 WO9716188 A1 WO 9716188A1
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WIPO (PCT)
Prior art keywords
nva
nle
lys
alkyl
aryl
Prior art date
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PCT/US1996/017134
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English (en)
Inventor
Alan D. Adams
A. Brian Jones
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Merck and Co Inc
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Merck and Co Inc
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Filing date
Publication date
Priority claimed from GBGB9603240.4A external-priority patent/GB9603240D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU74753/96A priority Critical patent/AU7475396A/en
Publication of WO1997016188A1 publication Critical patent/WO1997016188A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/14—All rings being cycloaliphatic
    • C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
    • C07C2602/28—Hydrogenated naphthalenes

Definitions

  • the present invention provides novel compounds, novel compositions, methods of their use and methods of their manufacture, where such compounds are generally pharmacologically useful as agents in therapies whose mechanism of action rely on the inhibition of peptide binding to major histocompatibility complex (MHC) class II molecules, and more particularly useful in therapies for the treatment and prevention of autoimmune diseases.
  • MHC major histocompatibility complex
  • a basic function of the immune system is to distinguish self from non-self, an activity carried out primarily by T cells. Failure of mechanisms which control the tolerance of T cells to self antigens and the prevention of activation of T cells by self antigens may lead to autoimmunity. In individuals afflicted with autoimmune diseases, an increased frequency of alleles for specific human leukocyte antigens (HLAs) are found, and it is believed that the disease-associated HLA molecules have the ability to bind the autoantigen and present it to T cells, thereby inducing and/or maintaining the autoimmune process.
  • HLAs human leukocyte antigens
  • Currently available immunosuppressive drugs are inadequate because of limited efficacy, lack of selectivity and considerable toxicity.
  • the present invention is directed to compounds which inhibit the binding of peptides to the major histocompatibility complex class II, a more selective target for therapeutic treatment and prevention of autoimmune diseases.
  • Major histocompatibility complex class II molecules are cell-surface giycoproteins that bind antigenic peptide fragments and display them at the cell surface to CD4- positive helper T-cells. The action of these molecules forms part of a pathway of the immune system for identifying and responding to foreign antigens.
  • antigen presenting cells internalize foreign proteins. Once internalized, the proteins are proteolytically degraded and short sequences of the degraded proteins are bound to MHC class II molecules in an endosomal compartment. These complexes of the short sequences bound to the MHC Class II molecule are then exposed on the cell surface where they initiate a series of immunogenic events.
  • MHC Class II proteins are synthesized and assembled in the endoplasmic reticulum as trimers composed of highly polymo ⁇ hic ⁇ and ⁇ -chain polypeptides and a non-polymo ⁇ hic invariant chain polypeptide.
  • the invariant chain prevents the premature binding of peptides to MHC class II.
  • the invariant chain contains a sequence that targets the ⁇ / ⁇ heterodimer into the low pH, protease-rich endosomal compartment. In this compartment, the invariant chain is removed, leaving the MHC class II ⁇ / ⁇ heterodimers free to bind antigenic peptides.
  • class I and class II histocompatibility proteins have different domain organizations but similar structures, with two membrane-proximal immunoglobulin-like domains and a membrane- distal peptide-binding site foimed by an eight stranded ⁇ -sheet and two ⁇ -helical regions. Polymo ⁇ hic residues in both class I and II proteins are clustered in the peptide-binding region and are responsible for the different peptide specificities observed for different histocompatibility proteins.
  • Class I histocompatibility proteins are specific for peptides of defined length, usually 8-10 residues and have allele-specific binding motifs characterized by strong preferences for a few side chains at some positions in the peptide, and wide tolerance for many side chains at the other positions. Class II histocompatibility proteins bind longer peptides with no apparent restriction on peptide length. Class II proteins also have allele specific motifs, which have been more difficult to characterize because of the difficulty in aligning peptide sequences of different lengths.
  • Antigen presenting cells expressing MHC class II molecules capture proteins from extracellular fluids.
  • APCs can take up antigens through surface immunoglobulin receptors, through Fc receptor-mediated intemalization of antibody/antigen complexes, or through bulk-phase endocytosis. Internalized antigens are then transported to endosomal compartments where they are digested into peptide fragments. A subset of these peptides can associate with a specific binding groove at the interface of MHC class II ⁇ and ⁇ -chain heterodimers. Most of the polymo ⁇ hisms in these proteins are located within this binding groove, so that each different MHC class II allele can bind a distinct, but overlapping, subset of antigenic peptides.
  • MHC class II/peptide complexes are then transported to the cell surface where they are recognized by T-cell receptors (TCRs) on CD4-positive T-cells.
  • TCRs T-cell receptors
  • This process is pivotal for the generation of both humoral and cellular immune responses.
  • MHC class II alleles are linked to susceptibility to many autoimmune diseases.
  • a prominent example of this is susceptibility to rheumatoid arthritis (RA) which is genetically associated with a small subset of related DR alleles (DR4Dw4, DR4Dw4, and DR1).
  • RA rheumatoid arthritis
  • MHC Class II proteins Autoimmune conditions are thought to involve the T-cell recognition of self-components by MHC Class II proteins, a situation which is normally avoided. This presentation generates an undesirable immune response to self. Since the sole function of MHC class II molecules is to present peptide antigens, the present invention is concerned with compounds which interfere with the binding of peptides to MHC class II molecules and a method of treating and preventing autoimmune diseases employing such compounds which interfere with the binding of peptides to MHC class II molecules associated with disease. Specifically blocking the formation of the MHC Class II/self- peptide complex is a manner of disrupting the aberrant process of the autoimmune disorder without globally depressing immune function. Hurtenbach et al., J. Exp. Med.
  • 177: 1499-1504 (1993) demonstrated that treatment with MHC class II complex-blocking peptide prevented autoimmune diabetes in non-obese diabetic mice. Further, Guery et al., J. Exp. Med. 177:1461 -1468 (1993) administered MHC class U binding peptides to mice and showed suppression of induction of T cell antibody responses.
  • the binding inhibitors of the present invention may prevent the presentation of self-peptides to autoreactive T-cells that drive the disease process.
  • An advantage of the immunotherapy and immunotherapeutic agents of the present invention is that they are very selective agents, targeting only certain alleles of MHC Class II, which may minimize the risk of opportunistic infections during long term treatment.
  • novel compounds of this invention are those of structural formula I:
  • the compounds of the present invention may be used in the treatment and prevention of autoimmune diseases, including rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus. There is no precedent in the literature for inhibition of autoimmune diseases, including rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus. There is no precedent in the literature for inhibition of autoimmune diseases, including rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus. There is no precedent in the literature for inhibition of autoimmune diseases, including rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus. There is no precedent in the literature for inhibition of autoimmune diseases, including rheumato
  • MHC Class II proteins by nonpeptides or pseudopeptides. Therefore it is an object of this invention to provide compounds that have activity in the inhibition of peptide binding to MHC Class II proteins. It is an additional object of this invention to provide methods of using the compounds of formula I for the treatment of autoimmune conditions such as rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus. It is a further object of this invention to provide pharmaceutical compositions for the compounds of formula I. Still another object of the present invention is to provide a method for in vitro inhibition of peptide binding of MHC Class II proteins.
  • novel compounds of this invention have the general structural formula I:
  • the bond represented by the dotted line "a" is selected from a single bond and a double bond; when “a” represents a double bond ⁇ l and X ⁇ are each hydrogen; when “a” represents a single bond, X 1 and X ⁇ are each H2, or ⁇ l and X ⁇ together are CH2, forming a cyclopropane ring with the "a" bond;
  • Z is selected from:
  • Y is selected from: (a) 0, and
  • Ci- 8 alkyl unsubstituted or substituted with one or two substituents selected from:
  • R is C2-6 alkyl, unsubstituted or substituted with one or two substituents selected from:
  • R4 is C2-6 alkyl, unsubstituted or substituted with one or two substituents selected from:
  • R 5 is selected from:
  • R 6 is selected from:
  • R 7 is selected from:
  • R x is independently selected from: C i -3alkyl and aryl; the bonds represented by the dotted lines "b", “c", and “d” are each independently selected from a single bond and a double bond; n is selected from zero, 1 and 2; W is selected from:
  • NHCOR5; Wl is selected from:
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and isomers thereof such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, etc.
  • Alkoxy represents an alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, e.g.
  • Alkoxycarbonyl represents a group of the form “alkyl-O-C(O)-" wherein the indicated number of carbon atoms refers to those of the alkyl residue.
  • Alkyl represents an alkyl group having the indicated number of carbon atoms attached through a -C(O)- bridge.
  • Sulfonyl represents an alkyl group having the indicated number of carbon atoms attached through a -S0 2 - bridge.
  • halogen and halo refer to F, Cl, Br and I.
  • the heterocyclic or aryl ring may be attached to the structural formula I at any nitrogen or carbon atom in the ring which results in the creation of a stable, uncharged structure.
  • EtOCO-Cha Lys Nva ⁇ [E,CH CH]Nle -NH2
  • Examples of compounds within this class include, but are not limited to, the following:
  • Z is selected from:
  • R2 is:
  • Ci- 8 alkyl unsubstituted or substituted with one substituent selected from:
  • R 3 is C2-6 alkyl, unsubstimted or substimted with one substituent selected from:
  • R4 is C2-6 alkyl, unsubstituted or substituted with one substituent selected from:
  • R 5 is selected from:
  • R 6 is selected from:
  • R 7 is selected from: (a) hydrogen, and
  • R 8 is independently selected from: Ci -3alkyl and aryl; the bonds i represented by the dotted lines “b”, “c", and “d” are all double bonds or are all single bonds; n is selected from zero, 1 and 2;
  • W is selected from:
  • W l is selected from:
  • NCORS aryl is selected from:
  • X 1 and ⁇ 2 are each hydrogen.
  • R l is 3-cyclohexyl propyl:
  • R2 is C ⁇ -8 alkyl, unsubstimted or substimted with one substituent selected from:
  • R 3 and R ⁇ each represent unsubstituted C2-6 alkyl; and at each occurrence, R* is independently selected from: Cl -3alkyl, and aryl.
  • R 3 is ethyl or propyl and R4 is propyl, butyl or isobutyl.
  • R l is 3-cyclohexyl propyl:
  • R2 is Ci- 8 alkyl, unsubstimted or substimted with one substituent selected from:
  • R 3 and R ⁇ each represent unsubstituted C2-6 alkyl; and at each occurrence, R* is independently selected from: C ⁇ _3alkyl, and aryl.
  • R 3 is ethyl or propyl and R4 is propyl, butyl or isobutyl.
  • R2 is: (a) Ci-8 alkyl, unsubstimted or substituted with one substituent selected from:
  • R 3 and R ⁇ each represent unsubstituted C2-6 alkyl;
  • R 5 is selected from:
  • R 6 is selected from:
  • R* is independently selected from: Cl -3alkyl, and aryl;
  • W is hydrogen
  • R 3 is ethyl or propyl and R4 is propyl, butyl, or isobutyl.
  • the compounds of the present invention are named according to the system described below, based on standard usage from the Journal of Biological Chemistry, and IUPAC's Nomenclature standards.
  • the compounds of the present invention are named by reference to a tetrapeptide.
  • Pl is the amino terminal residue, and may be protected by a group referred to as a "cap”.
  • P4 is the carboxy terminal residue.
  • Non-amino acid residues are generally named as one line alphanumeric structures constructed from accepted abbreviations. cHx(CH2)3-.
  • Analogs of peptides in which the amide bond is replaced with some other joining group are represented by the letter psi, ⁇ followed by the joining group in square brackets, placed between the residue symbols where the substitution is made. These are generally entered as one residue. Isosteres are single enantiomers and stereochemistry for the relevant center corresponds to the natural L isomer unless denoted otherwise.
  • the compounds of the present invention are of substantially non-peptide character, yet inhibit peptide binding MHC Class II proteins. Because the compounds of the present invention have substantially reduced peptide character relative to known inhibitors, the compounds of the present invention will be more likely to penetrate cellular membranes to access the Class II loading compartment within the cell, where competition for peptide binding is thought to occur.
  • the compounds of the present invention are expected to have better oral bioavailability and longer in vivo half life than intact peptides.
  • pharmaceutically acceptable salts of the compounds of formula I where a basic or acidic group is present on the structure.
  • the compounds of the present invention may be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, e
  • salts of the compounds of this invention include those foimed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine. diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
  • bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine. diethylamine, piperazine, tris(hydroxymethyl)aminome
  • a free acid by reacting a free acid with a suitable organic or inorganic base.
  • a suitable organic or inorganic base such as amino, an acidic salt, i.e. hydrochloride, hydrobromide, acetate, pamoate, and the like, can be used as the dosage form.
  • esters can be employed, e.g. acetate, maleate, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
  • any variable e.g., X, Y, Rl , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • Some of the crystalline forms for compounds of the present invention may exist as polymo ⁇ hs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • terapéuticaally effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disorder being treated.
  • the novel methods of treatment of this invention are for disorders known to those skilled in the art.
  • the term “mammal” includes humans.
  • the present invention has the objective of providing methods of treating and preventing autoimmune diseases including: rheumatoid arthritis, Type I diabetes, multiple sclerosis, lupus erythematosis, Graves disease and pemphigus by oral, systemic, parenteral or topical administration of the novel compounds of formula I either alone or in combination with other agents useful in treating autoimmune diseases.
  • such agents which may be used in combination with the novel compounds of structural formula (I) include, but are not limited to: aspirin; NSAIDs including fenoprofen, tolmetin, sulindac, meclofenamate, indomethacin, ibuprofen, naproxen, ketoprofen, piroxicam, flurbiprofen, and diclofenac; gold sodium thiomalate; aurothioglucose; auranofin; penicillamine; hydroxychloroquine; sulfasalazine, corticosteroids; methotrexate; azathioprine; and cyclophosphamide.
  • aspirin include, but are not limited to: aspirin; NSAIDs including fenoprofen, tolmetin, sulindac, meclofenamate, indomethacin, ibuprofen, naproxen, ketoprofen, piroxicam,
  • agents which may be used in combination with the novel compounds of structural formula (I) include, but are not limited to: insulin therapy.
  • agents which may be used in combination with the novel compounds of structural formula (I) include, but are not limited to: prednisone, dexamethazone, azathioprine, copolymer 1 , cyclophosphamide, interferon, plasmapheresis, and baclofen.
  • agents which may be used in combination with the novel compounds of structural formula (I) include, but are not limited to: antimalarials such as hydroxychloroquinine, chloroquine, and quinacrine; prednisone and methyl prenisolone; and cyclophosphamide.
  • antimalarials such as hydroxychloroquinine, chloroquine, and quinacrine
  • prednisone and methyl prenisolone include cyclophosphamide.
  • agents which may be used in combination with the novel compounds of structural formula (I) include, but are not limited to: systemic corticosteroids, prednisone, methotrexate, cyclophosphamide and azathioprine.
  • the present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment and prevention of the present invention.
  • treatment is intended to include ameliorating the autoimmune symptoms and/or arresting the progression of an autoimmune disease in an individual known to be, or believed to be suffering from an autoimmune disease.
  • prevention is intended to include ameliorating the underlying cause of an autoimmune condition in an individual who may not have begun to experience recognizable symptoms of an autoimmune condition, and arresting the progress of an autoimmune disease in a patient who has not begun to experience recognizable symptoms of an autoimmune condition.
  • compositions containing the present compounds as the active ingredient for use in the treatment of the above-noted conditions can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
  • the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection.
  • they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the compounds of the present invention may be used to prepare a medicament or agent useful in the treatment of autoimmune diseases, including: Graves' disease, rheumatoid arthritis, Type I diabetes, lupus erythematosis, pemphigus and multiple sclerosis.
  • autoimmune diseases including: Graves' disease, rheumatoid arthritis, Type I diabetes, lupus erythematosis, pemphigus and multiple sclerosis.
  • the daily dosage of the products may be varied over a range from 0.01 to 1 ,000 mg per adult human/per day.
  • the compositions are preferably provided in the form of tablets containing from 0.01 to 1 ,000 mg, preferably 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg./kg. to about 50 mg./kg. of body weight per day.
  • the range is more particularly from about 0.001 mg./kg. to 7 mg./kg. of body weight per day.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the compounds of the present invention may be administered in a pharmaceutical composition comprising the active compound in combination with a pharmaceutically acceptable carrier adapted for topical administration.
  • Topical pharmaceutical compositions may be, e.g., in the form of a solution, cream, ointment, gel, lotion, shampoo or aerosol formulation adapted for application to the skin.
  • These topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
  • the compounds of the present invention may be used together with agents known to be useful in treating autoimmune disease, discussed previously.
  • the active agents can be administered concurrently, or they each can be administered at separately staggered times.
  • the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed.
  • a physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
  • the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • carrier suitable pharmaceutical diluents, excipients or carriers
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated into the mixture.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like.
  • Other dispersing agents which may be employed include glycerin and the like.
  • glycerin for parenteral administration, sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • Topical preparations containing the active drug component can be admixed with a variety of carrier materials well known in the art, such as, e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, PPG2 myristyl propionate, and the like, to form, e.g., alcoholic solutions, topical cleansers, cleansing creams, skin gels, skin lotions, and shampoos in cream or gel formulations. See, e.g., EP 0 285 382.
  • the compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be foimed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention are receptor binding substrates intended to mimic four of the amino terminus proximal residues of known biologically relevant ligands.
  • the analogs described are therefore tetrapeptide mimics, or tetrapeptide register peptidomimetics.
  • the ring may be constructed by ring closure from unrelated intermediates by methods known in the literature. See ref. (18) for an example of this strategy.
  • either or both of the isomers of the trans cyclopropane unit could be useful as an amide bond geometry mimic, depending on the exact nature of the binding site involved.
  • Bodanszky M.; Bodanszky, A. The Practice of Peptide Synthesis. Springer Veriag, Berlin & New York, 1984.
  • the oxazolidinone (1.0 Eq, 0.02 mol, 3.54g) was dissolved in THF (20 mL) with Hexanoic anhydride ( 1.2 Eq, 0.024 mol, 5.6 ml) and LiCl (1.2 Eq, 0.024 mol, 1.02 g).
  • the reaction mix mre gelled with a mild exotherm when neat triethyl amine (1.2 Eq, 0.024 mol, 3.55 mL) was added.
  • the mixture was heated at reflux for 16 h to consumption of the oxazolidinone.
  • the reaction mixture was diluted EtOAc / H2 ⁇ and extracted four times with EtOAc. The organic phase was washed with 2 N HCl, satd. aq.
  • Step 2 Preparation of l -[trans-(2R)-n-BUTYL-(3S)-
  • Dibutylboron triflate was generated in situ and used immediately. Tributylboron (1.0 Eq, 20 mmol, 4.88 mL) was dissolved in CH2C12 (20 mL, Distilled from CaH2 under N2.) in a flask marked for 20 mL volume. Neat trifluoromethanesulfonic acid ( 1.0 Eq, 20 mmol, 1.77 mL) was added dropwise at a rate allowing controllable exotherm and gas evolution. Stirring was continued for 2 h at RT. Volume was made up to 20 mL with CH2CI2.
  • the imide (1.0 Eq, 17.5 mmol, 4.81 g product of Step 1 ) was dissolved in CH2CI2 ( 10 mL, distilled ) under N2 at 0°C.
  • the 1 M nBu2BOTf solution described above ( 1.1 Eq, 19.2 mmol, 19.2 mL) was added, followed by neat iPr2EtN ( 1.1 Eq, 19.2 mmol, 3.33 mL).
  • the resulting pale yellow solution was stirred at 0°C 45 minutes, and cooled to -78 0 Q 2-Hexenal ( 1.1 Eq, 19.2 mmol, 2.23 mL) was added neat at -78°C, maintained at -78°C 30 minutes and allowed to warm to RT.
  • the mixture was poured into 250 mL pH 7 phosphate buffer and 41 -
  • the crude product was redissolved in CH3OH (-100 mL) and cooled to 0°C.
  • Aqueous hydrogen peroxide ( ⁇ 5 mL, nominal 30%) was added and the mixmre allowed to stand 1 3/4 h at 0°C.
  • the mixture was reduced . vac. and diluted with CH2CI2 and H2O.
  • the organic phase was separated and washed with dil. aqueous bisulfite followed by saturated aqueous NH4CI.
  • the combined organic phases were dried and reduced . vac.
  • Step 3 Preparation of l ftrans-(2R)-n-BUTYL-(5S)-
  • the imide (product of Example 1 , Step 3) 1.0 Eq, 2.26 mmol, 1.2 g) was dissolved in THF (20 mL) and cooled to 0°C. Aqueous 2 M . LiOH (6.0 Eq, 13.6 mmol, 6.8 mL) was dropped in. The mixture was stirred at 0°C until the cleavage of the imide residue was complete as judged by TLC. The mixture was allowed to warm to RT and subsequently heated overnight at 55°C (16 h at 55°C). The mixture was cooled to RT and BOC-ON ( 5.0 Eq, 1 1.3 mmol, 2.8 g) was added. The mixture was stirred at RT for 24 h.
  • the reaction mixture was diluted with EtOAc and dil. aq. sodium bicarbonate and the aqueous phase washed 4 times with EtOAc. The organic phase from this wash was discarded. The aqueous phase was acidified to pH ⁇ 2, and extracted with EtOAc. The organic phase from the acidic extraction was dried over Na2S04 and reduced / ' . vac. The cmde acid was obtained as an oil sufficiently pure for further conversion. MS ESI 80% AcCN/ 0.1 % Aq TFA.
  • the BOC amino amide product of Example 1 was dissolved / suspended in CH2CI2 and cooled to 0°C. An equal volume of trifluoroacetic acid was dropped in, and the solution stirred at 0°C for 1 Hr. The mixture was reduced . vac. and excess TFA removed immediately by elution from a 12.5 X 700 mm Sephadex LH-20-100 column with CH3OH and reduction of fractions . vac. The product was obtained as an amo ⁇ hous solid. MS ESI 80% AcCN/ 0.1 % Aq TFA.
  • Step 1 Preparation of 1 -14-METHYLPENTANOYLH5R)- METHYL-(4SVPHENYLOXAZOLIDIN-2-ONE 47
  • the acyl oxazolidinone was prepared from (5R)-methyl- (4S)-Phenyl-oxazolidinone (5g) as for Example 1 , Step 1.
  • the product was obtained as a waxy solid.
  • Step 3 Preparation of 1 rtrans-(2R)-r2-METHYLPROPYL1-(5SV
  • the trichloroacetimidate intermediate was prepared from the aldol condensation product ( 1.1 g product of Example 2, Step 2) as per the general procedure of Example 1 , Step 3.
  • the product was obtained as an oil.
  • NvaHTE.CH CHlNle -(5R -METHYL-(4S - PHENYLOXAZOLIDPW-2-ONE IMIDE
  • Cupric Acetate (0.5 g) was dissolved in AcOH (50 mL) and heated to 100°C.
  • Granulated Zn (30 g, 30 Mesh) was added in one portion, and heating continued until the cupric acetate was consume as judged by color.
  • the mixture was decanted and washed twice with hot AcOH ( -50 mL each), followed by two careful washings with diethyl ether ( -50 mL each).
  • a fine red silt is decanted with the AcOH.
  • the brick red solid was dried under a stream of N2 and stored under N2. The material shows good reactivity for about one week.
  • the imide (63 mg, 0.1 19 mmol, product of Example 3, Step 1 ) was dissolved in 3 : 1 THF : H2 ⁇ (1.7 mL) and cooled to OOC. Hydrogen peroxide (4.0 Eq, nominal 30%, 54 ⁇ L) was added, followed by 2 M LiOH(2.0 Eq, 0.24 mmol, 1 19 ⁇ L). The mixture was stirred at 0°C until analytical TLC indicated complete cleavage of the imide. A large excess of LiOH ( 1.6 mL ) was added and the mixture was heated at 70 O C for 72 Hrs. The mixture was cooled to RT and BOC-ON (5.0 Eq, 0.59 mmol, 146 mg) was added.
  • Step 3 Preparation of ( ⁇ -BOCVNva ⁇ rcPr.translNle-NH? The ( ⁇ -BOC) protected amide was prepared from the
  • Typical amide bond couplings were run with EDC-HCl and HOBT as coupling reagents.
  • the starting acid 1.0-1.25 Eq
  • HOBT 2.0 Eq
  • the amine partner 1.0 Eq
  • DMF typically 500 ⁇ L for a 20-30 mg of the amine partner
  • iPr2EtN 1.0 Eq
  • Solid EDC-HCl 2.0 Eq
  • the reaction mixmre stirred to dissolve the reagents.
  • the mixture was stored ovemight at 0°C, and brought to RT for one hour.
  • the mixmre was poured into EtOAc / dil. aq. sodium bicarbonate and extracted 4 times EtOAc.
  • the organic phase was washed once with satd. aq. NH4CI, dried over
  • Step l Preparation of EtOCO-(L)Cha ( ⁇ -BOC)(L)Lys Nva ⁇ ftrans.cPrlNle-NH9 61 -
  • Step 1 from TFA-Nva ⁇ [trans,cPr]Nle-NH2 ( 8.0 mg, 0.024 mmol) and EtOCO- Cha ( ⁇ -BOC)Lys-OH ( mg, 0.035 mmol).
  • the coupling product was purified by chromatography on Si02 eluting with 8 : 1 : 1 toluene : EtOAc : iPrOH.
  • the desired tetrapeptide mimic was obtained as an amo ⁇ hous solid (7.0 mg, 44% of the theoretical yield).
  • Step 1 Preparation of ( ⁇ -BOC)( ⁇ -Nicotinoyl)(L)Lvs
  • NICOTINOYDLvs Nva ⁇ rE.CH CHlNle-NH9 TFA SALT 63
  • TFA salt product of Example 7, Step 3, 1.0 Eq, 0.028 mmol, 15.7 mg was dissolved in CH3OH (500 ⁇ L). Glacial AcOH (2.0 Eq, 0.056 mmol, 3.2 ⁇ L) and iPr2EtN (1.0 Eq, 0.028 mmol, 4.9 ⁇ L) were added, followed by 3-cyclohexylpropionaldehyde (Distilled, 1.0 Eq, 0.028 mmol, 4.3 ⁇ L). A 1.0 M . THF solution of NaCNBH3 ( 1.2 Eq, 0.034 mmol, 3.7 ⁇ L) was added at RT after brief stirring. Mild gas evolution was noted throughout the reaction. After 2 Hrs.
  • Step l Preparation of ( ⁇ -BOC)( ⁇ -Nicotinoyl)(L)Lys
  • Nicotinoyl)Lys-OH (25.8 mg, 0.074 mmol), the desired coupling product was obtained.
  • Step 3 Preparation of ⁇ -(3-Cyclohexylpropyl)( ⁇ -
  • Step 3 Preparation of ⁇ -(3-CyclohexylpropyD( ⁇ -
  • Nicotinovn(L)Lvs Nva ⁇ lE.CH CHlLeu-NH9
  • an oral composition of a compound of this invention 5 mg of a compound of structural formula I is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gelatin capsule.
  • the DR- peptide complexes (50 ⁇ L) are transferred to wells of a 96-well EIA plate precoated with LB3.1 , the monoclonal antibody which recognizes the DR alleles of MHC Class II, and blocked with PBS with fetal calf semm (FCS).
  • An additional 50 ⁇ L of 50 mM Tris, pH 7.0, containing 0.75% octyl glucoside is added to each well and the mixmre incubated ovemight at 4°C. Excess peptide is removed by washing with PBS containing 0.05% Tween 20 (Polyoxyethylene sorbitan monolaurate) and 0.01 % NaN3.
  • Europium-labeled streptavidin (Wallac Inc.) is added and incubated ovemight. After washing, complexes are measured by the addition of EnhanceTM buffer, the tradename for 0.1 M acetate phthalate buffer, pH 3.2, containing 0.1 % Triton X-100, tradename for polyoxyethylene ethers and other surface active compounds of Union Carbide Chemicals and Plastics Co., Inc.
  • EnhanceTM buffer the tradename for 0.1 M acetate phthalate buffer, pH 3.2, containing 0.1 % Triton X-100, tradename for polyoxyethylene ethers and other surface active compounds of Union Carbide Chemicals and Plastics Co., Inc.
  • LB3.1 ability of LB3.1 to bind DRIDwl and DR4Dw4 is shown to be equivalent by measuring the capacity of Ab-coated plates to bind serial dilutions of biotinylated DR molecules.
  • Europium streptavidin is used to measure the number of DR molecules bound as described for the peptide binding assay.
  • the inhibition assay format is identical to the procedure described above with the exception that the unlabeled antagonist is serially diluted and incubated with constant concentrations of biotinylated RMBP 90-102 (0.3 nM for DRIDwl or 0.9 nM for DR4Dw4) and the MHC class II proteins.
  • the concentration of unlabeled compound that prevents 50% of the labeled peptide from binding is the IC50 value.
  • the concentration of the biotinylated RMBP 90-102 in each assay is experimentally determined to be at least one- sixth of its measured ED50 to assure the inhibition was primarily measuring the binding characteristics of the competitor. This was confirmed by demonstrating that a two- or four fold reduction in the biotinylated agonist peptide did not alter the IC50 values obtained with unlabeled competitor proving that the receptor concentration was not limiting.

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Abstract

Cette invention concerne des composés représentés par la formule (I) qui sont des inhibiteurs des peptides se liant aux protéines de type II du complexe majeur d'histocompatibilité (CMH) et qui peuvent servir au traitement et à la prévention de maladies auto-immunes au nombre desquelles on compte la polyarthrite rhumatoïde, les diabètes de type I, la sclérose en plaques, le lupus érythémateux, le goitre exophtalmique et le pemphigus. La présente invention se rapporte en outre à de nouvelles compositions et à des procédés de traitement faisant usage de ces composés ainsi qu'à des procédés de fabrication des composés représentés par la formule (I).
PCT/US1996/017134 1995-10-30 1996-10-25 Nouveaux inhibiteurs de peptides se liant aux proteines de type ii du cmh Ceased WO1997016188A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002011714A3 (fr) * 2000-08-09 2003-08-14 Magnesium Diagnostics Inc Antagonistes du defaut de fixation de magnesium utilises en tant qu'agents therapeutiques et methodes de traitement des etats physiologiques anormaux
US7381413B1 (en) 1998-04-17 2008-06-03 University Of Vermont And State Agricultural College Methods and products related to metabolic interactions in disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003022A1 (fr) * 1986-10-31 1988-05-05 Pfizer Inc. Polypeptides de poids moleculaire relativement faible utilises comme inhibiteurs de la renine
EP0532466A2 (fr) * 1991-09-12 1993-03-17 Ciba-Geigy Ag Dérivés d'acide 5-amino-4-hydroxy-hexanoique et leur application comme agents thérapeutiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003022A1 (fr) * 1986-10-31 1988-05-05 Pfizer Inc. Polypeptides de poids moleculaire relativement faible utilises comme inhibiteurs de la renine
EP0532466A2 (fr) * 1991-09-12 1993-03-17 Ciba-Geigy Ag Dérivés d'acide 5-amino-4-hydroxy-hexanoique et leur application comme agents thérapeutiques

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Title
INT. J. PEPTIDE PROTEIN RES., Volume 46, issued 1995, BASAK et al., "Peptidyl Substrates Containing Unnatural Amino Acid at the P'1 Position are Potent Inhibitors of Prohormone Convertases", pages 228-237. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7381413B1 (en) 1998-04-17 2008-06-03 University Of Vermont And State Agricultural College Methods and products related to metabolic interactions in disease
US7211667B2 (en) 2000-08-09 2007-05-01 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
JP2004508299A (ja) * 2000-08-09 2004-03-18 マグネシウム　ダイアグノスティックス，インク． 治療薬としてのマグネシウム結合異常のアンタゴニストと、異常な生理的状態の治療方法
US6855826B2 (en) 2000-08-09 2005-02-15 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US7041829B2 (en) 2000-08-09 2006-05-09 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US7132537B2 (en) 2000-08-09 2006-11-07 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
WO2002011714A3 (fr) * 2000-08-09 2003-08-14 Magnesium Diagnostics Inc Antagonistes du defaut de fixation de magnesium utilises en tant qu'agents therapeutiques et methodes de traitement des etats physiologiques anormaux
US6664420B2 (en) 2000-08-09 2003-12-16 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US7405311B2 (en) 2000-08-09 2008-07-29 Magnesium Diagnostics, Inc. Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US7619097B2 (en) 2000-08-09 2009-11-17 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US7795450B2 (en) 2000-08-09 2010-09-14 Magnesium Diagnostics, Inc. Antagonist of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US7982048B2 (en) 2000-08-09 2011-07-19 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
US8129545B2 (en) 2000-08-09 2012-03-06 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states

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