WO1996013510A1 - Complexes de ruthenium et leur utilisation comme immunosuppresseurs - Google Patents

Complexes de ruthenium et leur utilisation comme immunosuppresseurs Download PDF

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Publication number
WO1996013510A1
WO1996013510A1 PCT/US1995/014067 US9514067W WO9613510A1 WO 1996013510 A1 WO1996013510 A1 WO 1996013510A1 US 9514067 W US9514067 W US 9514067W WO 9613510 A1 WO9613510 A1 WO 9613510A1
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Prior art keywords
containing ligands
group
complex
ligands
ruthenium
Prior art date
Application number
PCT/US1995/014067
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English (en)
Inventor
Cecilia M. Bastos
Timothy D. Ocain
Original Assignee
Procept, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/331,388 external-priority patent/US5512687A/en
Priority claimed from US08/482,308 external-priority patent/US5708022A/en
Application filed by Procept, Inc. filed Critical Procept, Inc.
Priority to AU40176/95A priority Critical patent/AU4017695A/en
Publication of WO1996013510A1 publication Critical patent/WO1996013510A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0046—Ruthenium compounds
    • C07F15/0053—Ruthenium compounds without a metal-carbon linkage

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 ruthenium complexes and their use as immunosuppressive agents to prevent or signif icantly reduce graft rej ection in organ and bone marrow transplantation.
  • the ruthenium complexes 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.
  • ruthenium complex of this invention can be treated with a ruthenium complex of this invention to alleviate symptoms associated with these disease states.
  • the ruthenium complexes have antiproliferative properties and in particular can inhibit cardiac smooth muscle cells. Based upon this, the ruthenium complexes can be used for the treatment of hyperproliferative vascular disorders, such as restenosis and atherosclerosis.
  • This invention is based upon the discovery that ruthenium complexes can inhibit antigen specific T lymphocyte proliferation in vitro .
  • the data suggest that ruthenium complexes have potential use as immunosuppressants to reduce undesirable immune responses in humans.
  • Ruthenium complexes 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 ruthenium complexes that have immunosuppressive properties of the general formula: [RuM m B b T t P p ]Z and physiologically acceptable salts thereof;
  • Ru is ruthenium having an oxidation state of 2, 3 or 4;
  • M is a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands, carbon containing ligands, oxygen containing ligands and halide (e.g., F, Br, Cl, I);
  • n 0, 1, 2, 3, 4 or 6;
  • b 0, 1, 2 or 3;
  • t 0, 1 or 2;
  • B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, sulfur containing ligands, carbon containing ligands, oxygen containing ligands and phosphorus containing ligands;
  • T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, carbon containing ligands, oxygen containing ligands and phosphorus containing ligands;
  • P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, carbon containing ligands, oxygen 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, for example a counterion selected from the group consisting of F-, Cl-, Br-, I-, NO 3 -, NH 4 + , NR 1 4 + , PF 6 - , BPh 4 -, SO 4 -2 , S 8 -2 , S 2 O 7 -2 ,
  • R 1 is a linear or branched alkyl (e.g., 1 to 8 carbon atoms) or aryl.
  • novel ruthenium complexes are represented by the general formula: [RuM 6 ]Z and physiologically acceptable salts thereof;
  • M is the same or different and is independently a heterocyclic aromatic amine, provided that for novel complexes of this formula the ligands cannot be 6-membered aromatic rings containing one or more nitrogens, such as pyridine, pyrazine, pyridazine or pyrimidine, or derivatives of these.
  • novel ruthenium complexes have the general formula:
  • Ru is ruthenium having an oxidation state of 2 or 3;
  • M, B and T are ligands (i.e., monodentate, bidentate and tridentate, respectively) that are heterocyclic aromatic amines (e.g., substituted or unsubstituted imidazole as defined below) coordinated to the ruthenium through aromatic nitrogens; provided that the ligand is not pyridine;
  • n 0, 1 or 3;
  • the coordination sphere of the metal center may contain all six ligands (referred to as monodentate) to be equivalent or a mixture of different ligands.
  • the mixture of ligands can consist of different monodentate ligands; a mixture of bidentate/monodentate in a ratio of 1:4 or 2:2; three bidentate ligands; a mixture of bidentate/
  • tridentate/monodentate in a ratio of 1:1:1; two tridentate ligands; or tridentate/monodentate in a 1:3 ratio; or a mixture of polydentate and bidentate in a ratio of 1:1; or a mixture of polydentate/monodentate in a 1:1 or 1:2 ratio depending on the nature of the polydentate ligand.
  • monodentate "monodentate”, “bidentate” and “tridentate” will have their generally accepted meaning in the art. That is, a monodentate ligand is defined as a chemical moiety or group which has one potential coordinating atom. More than one potential coordinating atom is termed a multidentate ligand 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.
  • Ruthenium complexes of this invention can contain a ruthenium metal center of different oxidation states, e.g., Ru(II), Ru(III) or Ru(IV).
  • the complex can inherently be neutral, i.e., it will not require counterion(s) to neutralize the overall charge of the complex.
  • the complex 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 physiological 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 render 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 per alkyl group, and the like; and organic and inorganic acids such as acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
  • inorganic cations such as sodium (Na + ), potassium (K + ), lithium (Li + ), and the like
  • organic bases such as mono-, di- and trial
  • the ruthenium complex can comprise six monodentate ligands which can contain nitrogen (e.g., heterocyclic aromatic amines, aliphatic amines), sulfur, phosphorus or oxygen groups.
  • suitable ligands include but are not limited to imidazole, pyridine, ammonia, triazole, picoline, pyrazole, quinoline, pyrazine, pyridazine, pyrimidine, quinoxaline, quinazoline, isoquinazoline, tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline, piperidine, phosphine, phosphite, thiolate, sulfoxide, alkoxide, phenolate and carboxylate.
  • a derivative is a ligand in which one or more of the hydrogen atoms has been substituted with a moiety, such as C1-C8 alkyl, C2-C8 alkenyl, hydroxy, nitro, amino, carboxyl, ester, di-C1-C8 alkyl amine, phenyl, benzyl, imidazole and combinations of these.
  • Preferred ligands are imidazole derivatives having the general formula:
  • R 2 and R 3 are independently selected from the group consisting of aryl, heteroaryl, linear and branched (e.g., 1 to 8 carbons) alkyl, -C(O)H, - (CH 2 ) n COOR 1 , -(CH 2 ) n SH, -(CH 2 ) n OH, -(CH 2 ) n NH 2 , -(CH 2 ) n OSO 2 , -(CH 2 ) n COH, -(CH 2 ) n COR', -(CH 2 ) n CONR', -(CH 2 ) n COOH, -(CH 2 ) n CH(X)(Y), H, Cl, Br, F, I and NO 2 ; where R 1 is a linear or branched alkyl (e.g., 1 to 8 carbon atoms) or aryl group; X is NH 2 ; Y is COOH and n is 0 to 8.
  • Preferred ligands also include pyridine derivatives having the following general formula:
  • R 10 is selected from the substituents defined above for R 2 and R 3 .
  • a ruthenium complex can be made having multidentate ligands, in combination with other multidentate ligands and/or monodentate ligands.
  • Suitable bidentate ligands (B) will include, but are not limited to, aliphatic amines (e.g., ethylene diamine, propylene diamine, 1,2-cyclohexane diamine and the corresponding alkylated amines thereof); heterocyclic aromatic amines (e.g., 2,2'-bipyridine, 1,10-phenanthroline);
  • pyridine based ligands e.g., 2-aminopicoline
  • pyrazole based ligands e.g., potassium-bis-pyrazolyl borate, bispyrazolyl methane
  • carboxylates e.g., 2-aminopicoline
  • imidazole based ligands having the general formula:
  • R 4 to R 9 are the same or different and are independently selected from the substituents defined above for R 2 and R 3 .
  • the ligand can be a tridentate ligand (T) such as aromatic heterocyclic amines (e.g., 2,2',6",2"-terpyridine, bis-(2-pyridylmethyl)amine); imidazole based ligands (e.g., bis-(2-imidazolylmethyl)amine); pyrazole based ligands (e.g., potassium tris pyrazolyl borate); macrocyclic amines (e.g., 1,4,7-triazacyclononane); macrocyclic sulfur based ligands (e.g., 1,4,7-trithiacyclononane and 2-(arylazophenyl) thio ether); and macrocyclic oxygen containing ligands Na ⁇ (C 5 H 5 )Co[P(O)R 2 ] 3 ⁇ .
  • T tridentate ligand
  • the ligand can be a polydentate ligand (P) such as nitrogen containing ligands (e.g., 1,4,7,10-tetraazacyclododecane; 1,4,8,11-tetraazacyclotetradecane; 1,3,5,7-tetrakis-(2-(4-sec-butylpyridyl)imino)benzodipyrrole;
  • P polydentate ligand
  • nitrogen ligands e.g., 1,4,7,10-tetraazacyclododecane; 1,4,8,11-tetraazacyclotetradecane; 1,3,5,7-tetrakis-(2-(4-sec-butylpyridyl)imino)benzodipyrrole;
  • the invention also pertains to dimers and trimers of the ruthenium complexes described above.
  • the coordination sphere of the metal center contain monodentate ligands
  • n and m' are independently 0, 1, 2, 3 or 5;
  • b and b' are independently 0, 1 or 2;
  • Trimers will have the general formula:
  • n and m' are independently 0, 1, 2, 3 or 5;
  • n 0, 1, 2 or 4;
  • b, b' and b" are independently 0, 1 or 2;
  • t, t' and t" are independently 0 or 1.
  • Ruthenium complexes can be administered orally, parenterally (e.g. intramuscularly, intravenously, subcutaneously), topically, nasally or via slow releasing microcarriers 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.
  • Ruthenium complexes 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 in psoriasis and 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 ruthenium complexes, 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 ruthenium complexes can be administered to mammals other than humans for immunosuppression of mammalian autoimmune diseases.
  • Ruthenium complexes 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 peripheral blood lymphocyte
  • 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 ruthenium complexes's ability to interfere with antigen induced lymphocyte proliferation.
  • HSV herpes simplex virus
  • Rubella Rubella
  • TT tetanus toxoid
  • Ruthenium complexes 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 ruthenium complex in patient blood levels. The ability to closely monitor the amount of ruthenium complex provides a suitable means for controlling drug delivery to patients in both preclinical and clinical settings.
  • the ruthenium complexes have antiproliferative properties and in particular can inhibit cardiac smooth muscle cells. Based upon this, the ruthenium complexes can be used for the treatment of hyperproliferative vascular disorders, such as restenosis and atherosclerosis. See Table 2. The invention will be further illustrated by the following non-limiting Exemplification:
  • 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
  • PBL's were incubated at a density of 10 5 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
  • test wells containing PBL's were exposed to antigen, along with various dilutions of the ruthenium complexes solutions, as shown in Table 1.
  • 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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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveaux complexes de ruthénium et leur utilisation comme immunosuppresseurs pour prévenir ou sensiblement réduire le rejet des greffes lors de transplantation d'organes ou de moelle épinière. Lesdits complexes peuvent également être utilisés comme immunosuppresseurs dans des maladies auto-immunes induites par le lymphocyte T, telles que le diabète, et pour soulager le psoriasis et l'eczéma de contact. Ces complexes peuvent également servir pour le traitement de maladies vasculaires hyperprolifératives.
PCT/US1995/014067 1994-10-28 1995-10-30 Complexes de ruthenium et leur utilisation comme immunosuppresseurs WO1996013510A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU40176/95A AU4017695A (en) 1994-10-28 1995-10-30 Ruthenium complexes and their use as immunosuppressive agents

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US33120494A 1994-10-28 1994-10-28
US08/331,204 1994-10-28
US08/331,388 US5512687A (en) 1994-10-28 1994-10-28 Compounds for inhibiting immune response
US08/331,388 1994-10-28
US47252595A 1995-06-07 1995-06-07
US08/482,308 1995-06-07
US08/482,308 US5708022A (en) 1994-10-28 1995-06-07 Method for inhibiting immune response
US08/472,525 1995-06-07

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6750251B2 (en) 1999-10-27 2004-06-15 The University Court, The University Of Edinburgh (Uk) Half-sandwich ruthenium (II) compounds comprising nitrogen containing ligands for treatment of cancer
US6936634B2 (en) 2000-06-30 2005-08-30 The University Court, The University Of Edinburgh (Uk) Ruthenium (II) compounds for use in the therapy of cancer
JP2007516239A (ja) * 2003-11-20 2007-06-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 特に複分解反応生成物からの、遷移金属の除去方法
WO2007089929A2 (fr) * 2006-01-31 2007-08-09 E. Heller & Company Composes d'osmium destines au traitement du psoriasis
US8216582B2 (en) 2006-06-23 2012-07-10 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in cancer
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
US8580257B2 (en) 2008-11-03 2013-11-12 Alethia Biotherapeutics Inc. Antibodies that specifically block the biological activity of kidney associated antigen 1 (KAAG1)
US8618293B2 (en) 2007-06-19 2013-12-31 Roche Diagnostics Operations, Inc. Redox mediators
US8937163B2 (en) 2011-03-31 2015-01-20 Alethia Biotherapeutics Inc. Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US10626432B2 (en) 2015-04-30 2020-04-21 Inside Biometrics International Limited Electron transfer agent
US11084872B2 (en) 2012-01-09 2021-08-10 Adc Therapeutics Sa Method for treating breast cancer

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6979681B2 (en) 1999-10-27 2005-12-27 University Court, The University Of Edinburgh Half-sandwich ruthenium (II) compounds comprising nitrogen containing ligands for treatment of cancer
US6750251B2 (en) 1999-10-27 2004-06-15 The University Court, The University Of Edinburgh (Uk) Half-sandwich ruthenium (II) compounds comprising nitrogen containing ligands for treatment of cancer
US6936634B2 (en) 2000-06-30 2005-08-30 The University Court, The University Of Edinburgh (Uk) Ruthenium (II) compounds for use in the therapy of cancer
JP2007516239A (ja) * 2003-11-20 2007-06-21 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 特に複分解反応生成物からの、遷移金属の除去方法
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection
WO2007089929A2 (fr) * 2006-01-31 2007-08-09 E. Heller & Company Composes d'osmium destines au traitement du psoriasis
WO2007089929A3 (fr) * 2006-01-31 2007-10-18 Heller E & Co Composes d'osmium destines au traitement du psoriasis
US8216582B2 (en) 2006-06-23 2012-07-10 Alethia Biotherapeutics Inc. Polynucleotides and polypeptide sequences involved in cancer
US8618293B2 (en) 2007-06-19 2013-12-31 Roche Diagnostics Operations, Inc. Redox mediators
US8580257B2 (en) 2008-11-03 2013-11-12 Alethia Biotherapeutics Inc. Antibodies that specifically block the biological activity of kidney associated antigen 1 (KAAG1)
US9855291B2 (en) 2008-11-03 2018-01-02 Adc Therapeutics Sa Anti-kidney associated antigen 1 (KAAG1) antibodies
US8937163B2 (en) 2011-03-31 2015-01-20 Alethia Biotherapeutics Inc. Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US9393302B2 (en) 2011-03-31 2016-07-19 Alethia Biotherapeutics Inc. Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US9828426B2 (en) 2011-03-31 2017-11-28 Adc Therapeutics Sa Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US10597450B2 (en) 2011-03-31 2020-03-24 Adc Therapeutics Sa Antibodies against kidney associated antigen 1 and antigen binding fragments thereof
US11084872B2 (en) 2012-01-09 2021-08-10 Adc Therapeutics Sa Method for treating breast cancer
US10626432B2 (en) 2015-04-30 2020-04-21 Inside Biometrics International Limited Electron transfer agent

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