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WO1996040170A2 - Composes contenant des metaux et leur utilisation pour inhiber la reponse immunitaire - Google Patents

Composes contenant des metaux et leur utilisation pour inhiber la reponse immunitaire Download PDF

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Publication number
WO1996040170A2
WO1996040170A2 PCT/US1996/005942 US9605942W WO9640170A2 WO 1996040170 A2 WO1996040170 A2 WO 1996040170A2 US 9605942 W US9605942 W US 9605942W WO 9640170 A2 WO9640170 A2 WO 9640170A2
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Prior art keywords
containing ligands
group
compound
bis
ligands
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PCT/US1996/005942
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English (en)
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WO1996040170A3 (fr
Inventor
Cecilia M. Bastos
Timothy D. Ocain
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Procept Inc
Original Assignee
Procept Inc
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Filing date
Publication date
Application filed by Procept Inc filed Critical Procept Inc
Publication of WO1996040170A2 publication Critical patent/WO1996040170A2/fr
Publication of WO1996040170A3 publication Critical patent/WO1996040170A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof

Definitions

  • Immunosuppressive agents are also indicated in the treatment of autoimmune diseases such as rheumatoid arthritis or type I diabetes mellitus.
  • autoimmune diseases such as rheumatoid arthritis or type I diabetes mellitus.
  • psoriasis This disease is characterized by erythematous patches of skin accompanied by discomfort and itching. Hyperplasia of the epidermis involving proliferation of keratinocytes is also a hallmark feature of psoriasis.
  • An inflammatory component is suggested by: (i) the finding of lymphocytic infiltration of epidermis, and (ii) the fact that immunosuppressive agents such as cyclosporin and corticosteroids have beneficial effect on the disease.
  • This invention relates to the use of compounds as immunosuppressive agents to prevent or significantly reduce graft rejection in organ and bone marrow transplantation.
  • the compounds can also be used as an immunosuppressant drug for T lymphocyte mediated autoimmune diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis, lupus erythematosus and steroid resistant asthma.
  • T lymphocyte immunosuppressive properties may also be useful in inhibiting the proliferation of cardiac smooth muscle cells. Based upon this, it is expected that the compounds can be used for the treatment of hyperproliferative vascular disorders, such as restenosis and atherosclerosis.
  • the invention also provides a method for coadministra- tion of the compounds described herein with agents designed for gene therapy. It is believed that the use of the compounds of this invention may suppress the immune system and reduce/minimize an immune response against the gene delivery vehicle, so that therapeutic levels of transgene expression can be achieved in an animal or human.
  • This invention is based upon the discovery that certain compounds can inhibit antigen specific T lymphocyte proliferation, in vitro .
  • the data suggest that these compounds have potential use as immunosuppressants to reduce undesirable immune responses in humans.
  • the compounds of this invention can be used to facilitate organ transplantation, and to treat human autoimmune disorders where the specific activation of T cells is responsible for, or contributes to the pathology and progression of the diseases, such as diabetes, rheumatoid arthritis, multiple sclerosis, lupus erythematosus and steroid resistant asthma.
  • This invention pertains to compounds that have immunosuppressive properties of the general formula: [ML 1 B h T t P p ]Z and physiologically acceptable salts thereof;
  • M is selected from the group consisting of iridium (Ir), palladium (Pd), chromium (Cr), iron (Fe), technitium (Tc), rhenium (Re), cobalt (Co), osmium (Os), manganese (Mn), copper (Cu), nickel (Ni), platinum (Pt) and rhodium (Rh), having an oxidation state of 2, 3 or 4 depending upon the nature of M;
  • b 0, 1 or 2;
  • t is 0 or 1;
  • p is 0 or 1;
  • p is 0 or 1;
  • each L is independently a monodentate Iigand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands, oxygen containing ligands, carbon containing ligands and halide (e.g., F, Cl, Br, I);
  • each B is independently a bidentate Iigand selected from the group consisting of nitrogen containing ligands (e.g., aliphatic amines, heterocyclic aromatic amines), sulfur containing ligands, carbon containing ligands, oxygen containing ligands and phosphorus containing ligands;
  • nitrogen containing ligands e.g., aliphatic amines, heterocyclic aromatic amines
  • sulfur containing ligands e.g., carbon containing ligands, oxygen containing ligands and phosphorus containing ligands
  • each T is independently a tridentate Iigand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, carbon containing ligands, oxygen containing ligands and phosphorus containing ligands;
  • each P is independently a polydentate Iigand selected from the group consisting of nitrogen containing ligands, oxygen containing ligands, carbon containing ligands, sulfur containing ligands and phosphorus containing ligands;
  • Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral, e.g., a counterion selected from the group consisting of F-, Cl-, Br-, I-, NO 3 -, NH 4 + , NR 4 + , PF 6 -, BPh 4 -, SO 4 -2 , S 8 -2 , S 2 O 7 -2 , BF 4 -, H + , CF 3 SO 3 -, Na + , K + , Li + , ClO 4 - and RImH + , where Im is imidazole; and organic and inorganic salts such as acetate, lactate, citrate, tartarate, succinate, maleate, malonate, gluconate, hydroch- loride, hydrobromide, phosphorate, nitrate, sulfate, trifluoromethansulfonate and methanesulfonate; wherein R is a linear or
  • the metal center When the metal center has four coordinating atoms then it may contain four equivalent ligands (referred as mono- dentate) or a mixture of ligands.
  • the mixture of ligands may contain different monodentate ligands, or a mixture of bidentate/ monodentate in a 1:2 ratio, or a mixture of bidentate ligands, or a mixture of tridentate/monodentate in a 1:1 ratio or a tetradentate Iigand.
  • the metal center may contain six equivalent ligands (referred as monodentate) or a mixture of different ligands.
  • the mixture of ligands may contain monodentate ligands, or a mixture of bidentate/ monodentate Iigand in a 1:4 or 2:2 ratio, or a mixture of tridentate/monodentate in a 1:3 ratio, or a mixture of tridentate/bidentate/monodentate in a 1:1:1 ratio, or a mixture of polydentate/monodentate in a 1:1 or 1:2 depending on the nature of the polydentate Iigand, or a mixture of a polydentate/bidentate in a 1:1 ratio, or three bidentate ligands or two tridentate ligands.
  • a monodentate Iigand is defined as a chemical moiety or group which has one potential coordinating atom. More than one potential coordinating atom is termed a polydentate Iigand where the number of potential coordinating atoms is indicated by the terms bidentate, tridentate, etc.
  • Ligands that are protonated are well within the scope of the invention.
  • Compounds of this invention can contain a metal center of different oxidation states, e.g., 2, 3 or 4.
  • the complex can inherently be neutral, i.e., it will not require counterion(s) to neutralize the overall charge of the complex.
  • the compounds can contain counterion (s) of appropriate charge to render the overall charge of the complex neutral and optionally to enhance solubility of the complex in a physiologically environment.
  • the number of counterions e.g., 1 to 5 counterions that are the same or different from each other) will be that which is required to neutralize the overall charge of the complex.
  • Counterions which result in physiologically acceptable salts of the complexes, including protonated salts thereof, are within the scope of this invention and include but are not limited to salts derived from inorganic cations such as sodium (Na + ), potassium (K + ), lithium (Li + ), and the like; organic bases such as mono-, di- and trialkyl amines of 1-8 carbon atoms, per alkyl group and mono-, di- and trihydroxyalkyl amines of 1-8 carbon atoms peralkyl group, and the like; and organic and inorgan- ic acids such as acetate, lactate, citrate, tartarate, succinate, maleate, malonate, gluconate, hydrochloride, hydrobromide, phosphorate, nitrate, sulfate, trifluoro- methansulfonate, methanesulfonate, and similarly known acceptable acids.
  • inorganic cations such as sodium (Na + ), potassium (K + ), lithium (
  • Suitable monodentate ligands (L) comprising aliphatic and aromatic amines include but are not limited to imidazole (Im), pyridine (py), ammonia, triazole, pyrazole, quinoline, pyrazine, pyridazine, pyrimidine, quinoxaline, quinazoline, piperidine, phosphine, phosphite, thiolate, sulfoxide, nitrogen, water, halide, alkoxide, phenolate and carboxylic acids. Derivatives of these ligands can also be incorporated into the complex in various combinations with the non-substituted ligands.
  • a derivative is a Iigand in which one or more of the hydrogen atoms has been substituted with a moiety, such as C1-C8 alkyl, C3-C8 cyclic alkyl, C2- C6 alkenyl, aryl or substituted aryl, hydroxyl, carboxylate, C1-C8 linear, branched or cyclic amine, nitro, ester, carbonyl, phenyl, carboxyl, benzyl, thio and combinations of these.
  • a preferred Iigand is methylimidazole.
  • Suitable bidentate ligands (B) will include, but are not limited to, aliphatic amines (e.g., ethylenediamine (en), propylenediamine, 1, 2-cyclohexanediamine and the corresponding alkylated amines thereof); heterocyclic aromatic amines (e.g., 2,2'-bipyridine (bipy), 1,10-phenanthroline); pyridine based ligands (e.g., 2-aminopicoline); pyrazole based ligands (e.g., potassium-bis-pyrazolyl borate, bis- pyrazolyl methane); carboxylates; and bis-phosphines (e.g., 1,2-bis (dimethylphosphino) methane).
  • aliphatic amines e.g., ethylenediamine (en), propylenediamine, 1, 2-cyclohexanediamine and the corresponding alkylated amines thereof
  • tridentate ligands examples include but are not limited to aliphatic amines (diethylenetriamine, dipro- pylenetriamine, 1,4,7-triazacyclononane, 1,4,7-triazacyclo- decane), aromatic amines [2,2' ,6",2"-terpyridine, bis-(2- pyridylmethyl) amine, bis-(2-imidazolylmethyl) amine, potassium tris-pyrazolyl borate, tris-pyrazolyl methane], oxygen based ligands (iminodiacetic acid, nitrilotriacetic acid, triethanol amine, bis- (3-methylphenoxy) amine), and sulfur based ligands (1,4,7-trithiacyclononane, 1,4,7- trithiacyclodecane, 2-(arylazophenyl) thioether).
  • aliphatic amines diethylenetriamine, dipro- pylenetriamine, 1,4,7-triaza
  • polydentate ligands include but are not limited to nitrogen containing ligands [e.g., 1,4,7,10- tetrazacyclododecane; 1,4,8,11-tetraazacyclotetradecane; tris- (2-pyridylmethyl) amine; tris-(2-imidazolylmethyl) amine]; sulfur containing ligands (l,4,8,11-tetrathiacyclo- tetradecane, 1,4,7,10-tetrathiacyclotridecane);andphosphorus containing ligands [ ⁇ , ⁇ '-bis-(bis-(2-diphenylphosphino- ethyl) amino) ethane and ⁇ , ⁇ '-bis-(bis-(2-diphenylphosphino)- m-xylene].
  • nitrogen containing ligands e.g., 1,4,7,10- tetrazacyclododecane; 1,4,8,11-t
  • Compounds of this invention can be administered orally, parenterally (e.g. intramuscularly, intravenously, subcuta- neously), topically, nasally or via slow releasing micro- carriers in dosage formulations (e.g., therapeutically effective amount) containing a physiologically acceptable vehicle and optional adjuvants and preservatives.
  • Suitable physiologically acceptable vehicles include saline, sterile water, creams, ointments, solutions, gels, pastes, emulsions, lotions, oils, solid carriers and aerosols.
  • the immunosuppressant compounds can be applied topically as a cream or ointment to locally deliver immunosuppressive concentrations of the drug without significant systemic exposure.
  • Topical application may be the ideal way to deliver the compound for psoriasis and perhaps other inflammatory skin diseases such as contact dermatitis and pemphigus vulgaris.
  • the specific dosage level of active ingredient will depend upon a number of factors, including biological activity of the compound, age, body weight, sex, general health, severity of the particular disease to be treated and the degree of immune suppression desired, as well as appropriate pharmacokinetic properties. It should be understood that the compounds described herein can be administered to mammals other than humans for immunosup- pression of mammalian autoimmune diseases.
  • the immunosuppressant compounds can be administered in combination with other drugs to boost the immunosuppressive effect.
  • Compounds that can be coadministered include steroids (e.g. methyl prednisolone acetate), NSAIDS and other known immunosuppressants such as azathioprine, 15- deoxyspergualin, cyclosporin, mizoribine, mycophenolate mofetil, brequinar sodium, leflunomide, FK-506, rapamcyin and related molecules. Dosages of these drugs will also vary depending upon the condition and individual to be treated.
  • the assay used to measure T cell growth inhibition was a human peripheral blood lymphocyte (PBL) proliferation assay using standard procedures known in the art. PBL's were chosen due to their known ability to proliferate in the presence of antigens derived from herpes simplex virus (HSV) , Rubella or tetanus toxoid (TT). PBL growth inhibition was measured in terms of the compound's ability to interfere with antigen induced lymphocyte proliferation.
  • HSV herpes simplex virus
  • TT tetanus toxoid
  • the compounds of this invention can be used to produce antibodies (e.g., polyclonal and monoclonal) against the complexes. Methods for making antibodies are well known.
  • the antibodies can be used as a diagnostic tool for monitoring the amount of the immunosuppressant compound in patient blood levels. The ability to closely monitor the amount of immunosuppressant provides a suitable means for controlling drug delivery to patients in both preclinical and clinical settings.
  • T lymphocyte immunosuppressive properties may also be useful in inhibiting the proliferation of cardiac smooth muscle cells. Based upon this, it is expected that the compounds can be used for the treatment of hyperproliferative vascular disorders, such as restenosis and atherosclerosis.
  • the invention also provides a method for coadministra- tion of the compounds described herein with agents designed for gene therapy. It is believed that the use of the compounds of this invention may suppress the immune system and reduce/minimize an immune response against the gene delivery vehicle, so that therapeutic levels of transgene expression can be achieved in an animal or human. Any type of gene therapy delivery vehicle can be coadministered, such as those well known in the art. Concurrent adminstration of the gene therapy delivery vehicle and the compounds of this invention, either as a single unit dose or taken individual- ly, is preferred.
  • lymphocytes were prepared by first separating them from the blood samples of several donors by Ficoll gradient separation as described by standard procedure known in the art. The isolated lymphocytes were then grown in RPMI 1640 medium containing 5% human AB serum, glutamine (2mM) , penicillin/streptomycin, 100 U/ml/100 ⁇ g/ml sodium pyruvate (ImM) and HEPES buffer (lOmM).
  • PBL's were incubated at a density of 10 s per 200 ⁇ l of medium per well of a 96-well plate.
  • Tetanus toxoid (TT; Connaught Labs, Willow Dale, ON) was used as a stimulating antigen at a concentration of 5 LF/ml.
  • test wells containing PBL's were exposed to antigen, along with various dilutions of the solutions containing the compound, as shown in the Table.
  • TT antigen/compounds exposed PBL's were pulsed with 1 ⁇ Ci/well of 3 H-thymidine on day 5 using a standard procedure known in the art.
  • the cells were then harvested 16 hours later onto a glass fiber filter using a TOMTEC cell harvester.
  • Thymidine incorporation was measured by liquid scintillation counting using a Beta plate counter (Pharmacia, Inc., Piscataway, N.J.).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention porte sur l'utilisation de composés en tant qu'immunodépresseurs servant à empêcher ou à diminuer de manière significative le rejet des greffons dans les greffes d'organe ou de moelle osseuse. Les composés de l'invention peuvent également s'utiliser comme immunodépresseurs dans les maladies auto-immunes à médiation thymodépendante, telles que le diabète, et peuvent être aussi bénéfiques pour soulager le psoriasis et l'eczéma de contact. Les composés peuvent également servir à des fins thérapeutiques dans le traitement des maladies vasculaires à évolution hyperchronique et pour réduire/supprimer la réponse immunitaire chez un patient subissant une thérapie génique.
PCT/US1996/005942 1995-06-07 1996-04-29 Composes contenant des metaux et leur utilisation pour inhiber la reponse immunitaire Ceased WO1996040170A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US47934195A 1995-06-07 1995-06-07
US47295295A 1995-06-07 1995-06-07
US08/472,952 1995-06-07
US08/479,341 1995-06-07

Publications (2)

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WO1996040170A2 true WO1996040170A2 (fr) 1996-12-19
WO1996040170A3 WO1996040170A3 (fr) 1997-02-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042338A1 (fr) * 1997-03-21 1998-10-01 Hoechst Aktiengesellschaft Prolongation de l'expression de proteines transgeniques par traitement immunomodulant
EP1391221A1 (fr) * 2002-08-23 2004-02-25 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Préparation pharmaceutique contenant des complexes de palladium pour le traitement du cancer et de maladies auto-immunes

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4000154A1 (de) * 1990-01-04 1991-07-11 Symbiotec Gmbh Chemotherapeutisches mittel, insbesondere zur behandlung von krebserkrankungen
US5512687A (en) * 1994-10-28 1996-04-30 Procept, Inc. Compounds for inhibiting immune response

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998042338A1 (fr) * 1997-03-21 1998-10-01 Hoechst Aktiengesellschaft Prolongation de l'expression de proteines transgeniques par traitement immunomodulant
EP1391221A1 (fr) * 2002-08-23 2004-02-25 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Préparation pharmaceutique contenant des complexes de palladium pour le traitement du cancer et de maladies auto-immunes
WO2004018043A1 (fr) * 2002-08-23 2004-03-04 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Preparation pharmaceutique contenant des composes a base de complexes de palladium et leur utilisation pour le traitement du cancer et d'affections auto-immunes

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Publication number Publication date
WO1996040170A3 (fr) 1997-02-13

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