WO1996013510A1 - Ruthenium complexes and their use as immunosuppressive agents - Google Patents
Ruthenium complexes and their use as immunosuppressive agents Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- containing ligands
- group
- complex
- ligands
- ruthenium
- Prior art date
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- 239000003018 immunosuppressive agent Substances 0.000 title claims abstract description 14
- 150000003303 ruthenium Chemical class 0.000 title abstract description 33
- 229940125721 immunosuppressive agent Drugs 0.000 title abstract description 7
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 11
- 230000001404 mediated effect Effects 0.000 claims abstract description 9
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 8
- 208000019553 vascular disease Diseases 0.000 claims abstract description 8
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 7
- 206010012442 Dermatitis contact Diseases 0.000 claims abstract description 5
- 208000010247 contact dermatitis Diseases 0.000 claims abstract description 5
- 229960003444 immunosuppressant agent Drugs 0.000 claims abstract description 5
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 4
- 230000001861 immunosuppressant effect Effects 0.000 claims abstract description 3
- 239000003446 ligand Substances 0.000 claims description 245
- 239000012327 Ruthenium complex Substances 0.000 claims description 42
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 41
- 229910052717 sulfur Inorganic materials 0.000 claims description 41
- 239000011593 sulfur Substances 0.000 claims description 41
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 40
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 40
- 229910052698 phosphorus Inorganic materials 0.000 claims description 40
- 239000011574 phosphorus Substances 0.000 claims description 40
- 229910052760 oxygen Inorganic materials 0.000 claims description 39
- 239000001301 oxygen Substances 0.000 claims description 39
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 34
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 29
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 23
- -1 hydroxy, nitro, amino, carboxyl Chemical group 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 18
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 18
- 229910000069 nitrogen hydride Inorganic materials 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052707 ruthenium Inorganic materials 0.000 claims description 17
- 230000007935 neutral effect Effects 0.000 claims description 15
- 230000003647 oxidation Effects 0.000 claims description 15
- 238000007254 oxidation reaction Methods 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 8
- 230000028993 immune response Effects 0.000 claims description 7
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 6
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 claims description 6
- 229930105110 Cyclosporin A Natural products 0.000 claims description 6
- 108010036949 Cyclosporine Proteins 0.000 claims description 6
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- 238000000034 method Methods 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 6
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- MDAXKAUIABOHTD-UHFFFAOYSA-N 1,4,8,11-tetraazacyclotetradecane Chemical compound C1CNCCNCCCNCCNC1 MDAXKAUIABOHTD-UHFFFAOYSA-N 0.000 claims description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
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- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
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- HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical compound C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 claims description 3
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- ZKWQSBFSGZJNFP-UHFFFAOYSA-N 1,2-bis(dimethylphosphino)ethane Chemical compound CP(C)CCP(C)C ZKWQSBFSGZJNFP-UHFFFAOYSA-N 0.000 claims description 2
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- ZKSQSTSLHFJTRH-UHFFFAOYSA-N 1,4,8,11-tetrakis(pyridin-2-ylmethyl)-1,4,8,11-tetrazacyclotetradecane Chemical compound C=1C=CC=NC=1CN(CCN(CC=1N=CC=CC=1)CCCN(CC=1N=CC=CC=1)CC1)CCCN1CC1=CC=CC=N1 ZKSQSTSLHFJTRH-UHFFFAOYSA-N 0.000 claims description 2
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- LDUCTLWCKOLAPM-UHFFFAOYSA-N 2-methyl-1h-pyridin-2-amine Chemical compound CC1(N)NC=CC=C1 LDUCTLWCKOLAPM-UHFFFAOYSA-N 0.000 claims description 2
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- HZQDCMWJEBCWBR-UUOKFMHZSA-N Mizoribine Chemical compound OC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 HZQDCMWJEBCWBR-UUOKFMHZSA-N 0.000 claims description 2
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- 239000013638 trimer Substances 0.000 description 2
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- NVOVSXGZALWAFS-UHFFFAOYSA-N 3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane Chemical compound C1NCCNCC2CNCCNCC1CNCCNC2 NVOVSXGZALWAFS-UHFFFAOYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 240000005589 Calophyllum inophyllum Species 0.000 description 1
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- 239000007995 HEPES buffer Substances 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010062049 Lymphocytic infiltration Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 201000011152 Pemphigus Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 229910019891 RuCl3 Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- 150000004703 alkoxides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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- 230000036765 blood level Effects 0.000 description 1
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- 230000010261 cell growth Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 210000005104 human peripheral blood lymphocyte Anatomy 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960001293 methylprednisolone acetate Drugs 0.000 description 1
- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- BLUYEPLOXLPVCJ-INIZCTEOSA-N n-[(1s)-2-[4-(3-aminopropylamino)butylamino]-1-hydroxyethyl]-7-(diaminomethylideneamino)heptanamide Chemical compound NCCCNCCCCNC[C@H](O)NC(=O)CCCCCCNC(N)=N BLUYEPLOXLPVCJ-INIZCTEOSA-N 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 201000001976 pemphigus vulgaris Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-M phenolate Chemical compound [O-]C1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-M 0.000 description 1
- 229940031826 phenolate Drugs 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
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- 125000005270 trialkylamine group Chemical group 0.000 description 1
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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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Abstract
Novel ruthenium complexes and their use of ruthenium complexes as immunosuppressive agents to prevent or significantly reduce graft rejection in organ and bone marrow transplantation are described. The ruthenium complexes can also be used as immunosuppressant drugs for T-lymphocyte mediated autoimmune diseases, such as diabetes, and may be useful in alleviating psoriasis and contact dermatitis. The ruthenium complexes can also be used therapeutically in the treatment of hyperproliferative vascular disease.
Description
RUTHENIUM COMPLEXES AND THEIR USE AS IMMUNOSUPPRESSIVE AGENTS
Background of the Invention
Replacement of defective or severely injured tissues and organs has been a medical objective as long as medicine has been practiced. Grafts from an individual to himself almost invariably succeed, and are especially important in the treatment of burn patients. Likewise, grafts between two genetically identical individuals almost invariably succeed. However, grafts between two genetically dissimilar individuals would not succeed without immunosuppressive drug therapies. The major reason for their failure is a T cell mediated immune response to cell-surface antigens that distinguish donor from host.
Immunosuppressive agents are also indicated in the treatment of autoimmune diseases such as rheumatoid arthritis or type I diabetes mellitus. One particular condition worth mentioning here is 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.
A number of drugs are currently being used or investigated for their immunosuppressive properties. Among these drugs, the most commonly used immunosuppressant is cyclosporin A. However, usage of cyclosporin has numerous side effects such as nephrotoxicity, hepatotoxicity and other central nervous system disorders. Thus, there is presently a need to investigate new immunosuppressive
agents that are less toxic but equally as effective as those currently available.
Summary of the Invention
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.
In another aspect, other diseases with suspected inflammatory components, such as psoriasis, contact dermatitis and hyperplasia of the epidermis, can be treated with a ruthenium complex of this invention to alleviate symptoms associated with these disease states.
It has also been demonstrated that 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.
Detailed Description of the Invention
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: [RuMmBbTtPp]Z and physiologically acceptable salts thereof;
wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein 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);
wherein m is 0, 1, 2, 3, 4 or 6;
wherein b is 0, 1, 2 or 3;
wherein t is 0, 1 or 2;
wherein p is 0 or 1;
wherein 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;
wherein 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;
wherein 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;
wherein when the complex is charged, then 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-, NO3-, NH4 +, NR1 4 +, PF6- , BPh4-, SO4 -2, S8 -2 , S2O7 -2,
RuCl4 -2, K+, Na+, Li+, ClO4- and R1ImH+, where Im is imidazole; and
wherein R1 is a linear or branched alkyl (e.g., 1 to 8 carbon atoms) or aryl.
In a preferred embodiment, novel ruthenium complexes are represented by the general formula: [RuM6]Z and physiologically acceptable salts thereof;
wherein 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.
In another embodiment, novel ruthenium complexes have the general formula:
[Ru(NH3)3MmBbTt]Z and physiologically acceptable salts thereof;
wherein Ru is ruthenium having an oxidation state of 2 or 3;
wherein 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;
wherein m is 0, 1 or 3;
wherein b is 0 or 1; and
wherein t is 0 or 1.
Examples of complexes which are covered by this formula are:
[Ru(NH3)3(Im)3]Cl3
[Ru(NH3)3(1-MeIm)3]Cl3.
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.
For the purposes of this application, the terms
"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). Depending upon the ligands, the complex can inherently be neutral, i.e., it will not require counterion(s) to neutralize the overall charge of the complex. Alternatively, 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. Some specific examples are listed above under the definition for Z.
In one embodiment, the ruthenium complex can comprise six monodentate ligands which can contain nitrogen (e.g., heterocyclic aromatic amines, aliphatic amines), sulfur, phosphorus or oxygen groups. Examples of 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. Derivatives of these ligands can also be incorporated into the complex in various combinations with the non-substituted ligands. 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:
Preferred ligands also include pyridine derivatives having the following general formula:
wherein R10 is selected from the substituents defined above for R2 and R3.
Examples of preferred ruthenium complexes having monodentate ligands are listed below.
[Ru(Im)6]Cl2 where Im = imidazole
[Ru(1-MeIm)6]Cl2 where 1-Melm = 1-methyl imidazole
[Ru(1-Melm)6](PF6)3
[Ru ( 1-MeIm) 6 ] Cl3
[Ru(Im)6]Cl3
trans-[Ru(NH3)4(Im) (py)]Cl3 where py = pyridine cis-[Ru(NH3)4(Im)2]Cl3
trans-[Ru(NH3)4(Im)2]Cl3
[Ru(NH3)5(L-his)]Cl3 where his = histidine
[Ru(NH3)5(py)]Cl(RuCl4)
cis-[Ru(NH3)4(py)2]Cl3
[Ru(NH3)5(4-pic)]Cl3 where pic = picoline
cis-[Ru(NH3)4(1-MeIm)2]Cl3 In another embodiment, 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; and bis-phosphines
(e.g., 1,2-bis(dimethylphosphino)ethane). Preferred are imidazole based ligands having the general formula:
where R4 to R9 are the same or different and are independently selected from the substituents defined above for R2 and R3.
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{(C5H5)Co[P(O)R2]3}.
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;
3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane; and,
1,4,8,11-tetrakis-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane); sulfur containing ligands (e.g.,
1,4,7,10-tetrathiacyclotridecane and 1,4,8,11-tetrathiacyclotetradecane); and phosphorus containing ligands
(e.g., α,α'-bis-(bis-(2-biphenylphosphino)ethyl)amino)ethane and α,α '-bis-(bis-(2-diphenylphosphino)m-xylene).
The invention also pertains to dimers and trimers of the ruthenium complexes described above. The coordination sphere of the metal center contain monodentate ligands
(that are the same or different from each other) or it can contains a mixture of monodentate, bidentate and/or tridentate ligands. The counterions are the same as those described above.
Dimers will have the general formula:
wherein the variables are described above and further wherein
m and m' are independently 0, 1, 2, 3 or 5;
b and b' are independently 0, 1 or 2; and
t and t' are independently 0 or 1.
Trimers will have the general formula:
wherein the variables are described above and further wherein
m and m' are independently 0, 1, 2, 3 or 5;
m" is 0, 1, 2 or 4;
b, b' and b" are independently 0, 1 or 2; and
t, t' and t" are independently 0 or 1.
General procedures for making monomeric ruthenium complexes include: Vogt, Jr. et al., Inorg. Chem., 4: 1157 (1965); Ford et al., J. Am. Chem. Soc., 90:1187 (1968); Marchant et al., Inorg. Chem., 16:2160 (1977); Sullivan et al., Inorg. Chem., 17:3334 (1978); Klassen et al.,
Inorg. Chem., 19:1977 (1980); Klassen et al., Inorg.
Chem., 14:2733 (1975); Leising et al., Inorg. Chem.,
29:4569, (1990); Bessel et al., J. Chem. Soc.. Dalton trans., pp. 1563 (1993); Bernhard and Sargeson, J. Chem. Soc. Chem. Commun., pp. 1516 (1985); Poon and Che, J.
Chem. Soc, Dalton trans., pp. 491 (1981); Walker and Taube, Inorg. Chem.. 20:2828 (1981); Mazzetto et al.,
Polyhedron. 12:971 (1993); Khan et al., Inorg. Chim. Acta, 189: 165 (1991); Keppler et al., Inorg. Chem., 26:844
(1987); and Kraus, Inorg. Chim. Acta.. 22:209 (1977).
General procedures for making dimeric and trimeric ruthenium complexes include: Dopplet and Meyer, Inorg. Chem.. 26:2027 (1987); Geselowitz et al., Inorg. Chem., 25:2015 (1986); Neubold et al., Inorg. Chem.. 21:459 (1989);
Sasaki et al., J. Am. Chem. Soc., 110: 6251 (1988); Smith et al., Inorg. Chem., 10:1943 (1971); Sudha et al., J. Am. Chem. Soc.. 32:3801 (1993); Weaver et al., J. Am. Chem. Soc.. 97:3039 (1975) and Emerson et al., J. Am. Chem.
Soc.. 115:11799 (1993).
It has now been discovered that the ruthenium complexes of this invention possess immunosuppressive activity as confirmed through a drug screen. Specific T cell proliferation was measured in response to antigen exposure in the presence or absence of ruthenium complexes. It was found that ruthenium complexes inhibited T cell proliferation by 50% (IC50) at a concentration of about 1 to 100 nM. This compares favorably with cyclosporin A, which has an IC50 at 20nM (Table 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'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.
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.
It has also been demonstrated that 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:
Examples
Example 1 - Preparation of [Ru(1-Melm)6]Cl2
RuCl3 (1.871 g, 9.04 mmol) was added slowly to 1-MeIm (10mL, 125 mmol, 14 eq.). The mixture was placed in a preheated oil bath (230°C), and the mixture was refluxed for 2 hours. The mixture was cooled down to room temperature and acetone (50-70 mL) was added to the mixture. The mixture was filtered and the solid washed with acetone (3 X 10 mL). The product was dried under vacuum.
The product was dissolved in MeOH (30 mL), and filtered over celite. The product was obtained as a light yellow crystalline (3.27 g, 55%) solid after triple crystallization from MeOH/ether.
[Ru(1-MeIm)6]Cl2 was characterized by X-ray crystallography, 1H NMR, UV/Vis and elemental analysis.
Example 2 - Preparation of [Ru(1-Melm)6]Cl3
[Ru(1-MeIm)6]Cl2 (0.405 g, .609 mmol) was dissolved in HCl (0.25 M, 30 mL) and H2O2 was added slowly until the starting material had disappeared (reaction followed by UV/Vis spectroscopy). The solvent was removed to dryness and the product was purified by recrystallization from MeOH/ether. The product was characterized by UV/Vis. Example 3 - Preparation of [Ru(NH3)3(1-Melm)3]Cl3
Zn/Hg was added to a previously degassed suspension of [Ru(NH3)3Cl3] (69.1 mg, 0.267 mmol) and 1-Melm (200 μL, 2.51 mmol) in HCl (0.1M, 15 mL). The mixture was stirred at room temperature (under Ar) for 20 hours. It was filtered over celite and H2O2 (30%, 2 drops) and HCl (1M, 1
mL) were added. The color of the solution turned from light yellow to orange. The mixture was stirred at room temperature for 1 hour and the solvent was removed to dryness. The mixture was redissolved in water (1 mL) and ethanol (400 mL) added, and then it was placed in the refrigerator overnight. The mixture was filtered, washed with ethanol (2 X 10 mL) and then dried under vacuum. The product was crystallized from water/ethanol/acetone. The product was obtained as an orange solid (53.7 mg, 37% yield). It was characterized by UV/Vis and elemental analysis.
Example 4 - PBL Antigen Specific Proliferation Assay
The 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 μg/ml sodium pyruvate
(1mM) and HEPES buffer (10mM).
For assay purposes, PBL's were incubated at a density of 105 per 200μl 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.
The test wells containing PBL's, were exposed to antigen, along with various dilutions of the ruthenium complexes solutions, as shown in Table 1.
Subsequently, TT antigen/ruthenium complexes exposed
PBL's were pulsed with 1 μCi/well of 3H-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.).
The results of the assay are shown in Table 1.
The assay used to determine inhibition of human coronary aortic smooth muscle cell proliferation was reported by Morris, Heart Lung Transplant 11(pt2):197 (1992). The results are shown in Table 2 below.
Equivalents
Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims:
Claims
1. A ruthenium complex of the general formula:
[RuM6]Z and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2 or 3;
wherein M is the same or different and is independently a monodentate ligand that is a heterocyclic aromatic amine;
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral; and
provided that the ligands cannot be 6-membered rings containing one or more nitrogens.
2. The ruthenium complex of Claim 1 wherein M is a heterocyclic aromatic amine selected from the group consisting of imidazole, triazole, pyrazole, quinoline, quinoxaline, quinazoline, tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline and their derivatives obtained by substituting for one or more hydrogen atoms with one or more of the following moieties C1-C8 alkyl, C2-C8 alkenyl, hydroxy, nitro, amino, carboxyl, ester, di-C1-C8 alkyl amine, phenyl, benzyl and combinations thereof.
3. The ruthenium complex of Claim 2 wherein the ruthenium complex is selected from the group consisting of:
a) [Ru(Im)6]Cl2 where Im = imidazole;
b) [Ru(1-MeIm)6]Cl2 where 1-Melm = 1-methyl imidazole; c) [Ru(1-Melm)6](PF6)3;
d) [Ru(1-MeIm)6]Cl3;
e) [Ru(Im)6]Cl3; and
f) [Ru(4-MeIm)6]Cl2. 4. A ruthenium complex of the general formula:
[Ru(NH3)3MmBbTt]Z and physiologically acceptable salts thereof;
wherein Ru is ruthenium having an oxidation state of 2 or 3;
wherein M, B and T are independently ligands that are heterocyclic aromatic amines coordinated to the ruthenium through aromatic nitrogens; provided that the ligand is not pyridine;
wherein m is 0, 1 or 3;
wherein b is 0 or 1; and
wherein t is 0 or 1;
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral 5. A ruthenium complex for use in preventing or reducing a T-lymphocyte mediated immune response of a mammal (e.g., autoimmune disease), wherein the ruthenium complex has the general formula:
[RuMmBbTtPp]Z and physiologically acceptable salt thereof;
wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein 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;
wherein m is 0, 1, 2, 3, 4 or 6;
wherein b is 0, 1, 2 or 3;
wherein t is 0, 1 or 2;
wherein p is 0 or 1;
wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, carbon containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands;
wherein 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; wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen containing ligands, carbon containing ligands, sulfur containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral. The ruthenium complex of Claim 5 wherein P is selected from the group consisting of 1,4,7,10-tetraazacyclododecane; 1,
4,8,11-tetraazacyclotetradecane; 1,3,
5,7-tetrakis-(2-(4-sec-butylpyridyl)imino)benzodipyrrole; 3,6,10,13,16,19-hexaazabicyclo[6.6.
6]eicosane; 1,4,8,11-tetrakis-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane); 1,4,7,10-tetrathiacyclotridecane and 1,4,8,11-tetrathiacyclotetradecane); α,α'-bis-(bis-(2-diphenylphosphino)ethyl)amino)ethane and α,α'-bis-(bis- (2-diphenylphosphino)m-xylene).
7. The ruthenium complex of Claim 5 having a structure that is selected from the group consisting of:
wherein Im is Imidazole, DMSO is dimethylsulfoxide, py is pyridine, en is ethylenediamine, Bzlm is benzimidazole, his is histidine, pic is picoline, ala is alanine, cyclam is 1,4,8,11-tetraazacyclotetradecane, Melm is methylimidazole, Ph is phenyl, and PPh is phenyl phosphine.
8. A ruthenium complex for use in preventing or reducing a T-lymphocyte mediated immune response in a mammal (e.g., autoimmune response), wherein the ruthenium complex has the general formula: [(RuMmBbTt)-O-(RuM'm,B'b,T't)]Z
and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein M and M' are independently a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands and oxygen containing ligands and halide;
wherein m and m' are independently 0, 1, 2, 3 or 5;
wherein b and b ' are independently 0 , 1 or 2 ; wherein t and t ' are independently 0 or 1 ;
wherein B is a bidentate l igand selected from the group consisting of aliphatic amines , heterocyclic aromatic amines , sulfur conta ining ligands , oxygen containing l igands and phosphorus containing ligands ; wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
9. The ruthenium complex of Claim 8, having a structure that is selected from the group consisting of:
[Ru2(μ-O)(NH3)8Cl2]Cl3;
[Ru2(μ-O)(NH3)8(HCO2)2]Cl3;
[Ru2(μ-O)(NH3)8(H2O)2](ClO4)5;
[Ru2O(OAc)2(py)6](PF6)2;
[Ru2O(OAc)2(Bipy)2(py)2](PF6)2; and
[Ru2O(Bipy)4(H2O)2](ClO4)4;
wherein py is pyridine and Bipy is 2,2'-bipyridine.
10. A ruthenium complex for use in preventing or reducing a T-lymphocyte mediated immune response of a mammal (e.g., autoimmune response), wherein the ruthenium complex has the general formula: 
and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein M, M' and M" are independently a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands, oxygen containing ligands;
wherein m and m' are independently 0, 1, 2, 3 or 5;
wherein m" is o, 1, 2 or 4 ;
wherein b, b' and b" are independently 0, 1 or 2; wherein t, t' and t" are independently 0 or 1; wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
11. The ruthenium complex of Claim 10, that is [Ru3O2(en)2(NH3)10]Cl6; wherein en is ethylenediamine.
12. A ruthenium complex for use in treating hyperproliferative vascular disorders, wherein the compound has the general formula:
[RuMmBhTtPp]Z and physiologically acceptable salt thereof; wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein 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;
wherein m is 0, 1, 2, 3, 4 or 6;
wherein b is 0, 1, 2 or 3;
wherein t is 0, 1 or 2;
wherein p is 0 or 1;
wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, carbon containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands;
wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, carbon containing ligand, oxygen containing ligands and phosphorus containing ligands; wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen containing ligands, carbon containing ligands, sulfur containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
13. Use of a ruthenium complex for the manufacture of a medicament (i) to prevent or reduce a T-lymphocyte mediated immune resonse (e.g., autoimmune response) of a mammal or (ii) to treat hyperproliferative vascular disorders; wherein the ruthenium complex has the general formula:
[RuMmBbTtPp]Z and physiologically acceptable salt thereof;
wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein 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;
wherein m is 0, 1, 2, 3, 4 or 6;
wherein b is 0, 1, 2 or 3;
wherein t is 0, 1 or 2;
wherein p is 0 or 1;
wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, carbon containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands;
wherein 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; wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen containing ligands, carbon containing ligands, sulfur containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
14. Use of a ruthenium complex for the manufacture of a medicament (i) to prevent or reduce a T-lymphocyte mediated immune response (e.g., autoimmune response) of a mammal or (ii) to treat hyperproliferative vascular disorders; wherein the ruthenium complex has the general formula: 
and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2 , 3 or 4;
wherein M and M' are independently a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands and oxygen containing ligands and halide;
wherein m and m' are independently 0, 1, 2, 3 or 5;
wherein b and b' are independently 0, 1 or 2; wherein t and t' are independently 0 or 1;
wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
15. Use of a ruthenium complex for the manufacture of a medicament (i) to prevent or reduce a T-lymphocyte mediated immune response (e.g., autoimmune response) of a mammal or (ii) to treat hyperproliferative vascular disorders; wherein the ruthenium complex has the general formula: 
and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2 , 3 or 4;
wherein M, M' and M" are independently a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands, oxygen containing ligands;
wherein m and m' are independently 0, 1, 2, 3 or 5;
wherein m" is 0, 1, 2 or 4;
wherein b, b' and b" are independently 0, 1 or 2; wherein t, t' and t" are independently 0 or 1; wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
16. A composition comprising a therapeutically effective amount of a ruthenium complex in a physiologically acceptable vehicle; wherein the ruthenium complex has the general formula: [RuMmBbTtPp]Z and physiologically acceptable salt thereof; wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein 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;
wherein m is 0, 1, 2, 3, 4 or 6;
wherein b is 0, 1, 2 or 3;
wherein t is 0, 1 or 2;
wherein p is 0 or 1;
wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, carbon containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands;
wherein 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; wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen containing ligands, carbon containing ligands, sulfur containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
17. A composition comprising a therapeutically effective amount of a ruthenium complex in a physiologically acceptable vehicle; wherein the ruthenium complex has the general formula: 
and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2 , 3 or 4;
wherein M and M' are independently a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands and oxygen containing ligands and halide;
wherein m and m' are independently 0, 1, 2, 3 or 5;
wherein b and b' are independently 0, 1 or 2; wherein t and t' are independently 0 or 1;
wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
18. A composition comprising a therapeutically effective amount of a ruthenium complex in a physiologically acceptable vehicle; wherein the ruthenium complex has the general formula: 
and physiologically acceptable salts thereof; wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein M, M' and M" are independently a monodentate ligand selected from the group consisting of nitrogen containing ligands, phosphorus containing ligands, sulfur containing ligands, oxygen containing ligands;
wherein m and m' are independently 0, 1, 2, 3 or 5;
wherein m" is 0, 1, 2 or 4;
wherein b, b' and b" are independently 0, 1 or 2; wherein t, t' and t" are independently 0 or 1; wherein B is a bidentate ligand selected from the group consisting of aliphatic amines, heterocyclic aromatic amines, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; wherein T is a tridentate ligand selected from the group consisting of nitrogen containing ligands, sulfur containing ligands, oxygen containing ligands and phosphorus containing ligands; and wherein when the complex is charged then Z is at least one counterion of appropriate charge to render the overall charge of the complex neutral.
19. The ruthenium complex, use or composition according to any of Claims 5 to 18 wherein M is a nitrogen containing ligand selected from the group consisting of imidazole, pyridine, ammonia, triazole, pyrazole, quinoline, pyrazine, pyridazine, picoline, pyrimidine, quinoxaline, quinazoline, tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline, piperidine and their derivatives obtained by substituting for one or more hydrogen atoms with one or more of the following moieties C1-C8 alkyl, C2-C8 alkenyl, hydroxy, nitro, amino, carboxyl, ester, di-C1-C8 alkyl amine, phenyl, benzyl, imidazole and combinations thereof.
20. The ruthenium complex, use or composition according to
Claims 2, 4 or 19 wherein the imidazole has the general formula: 
where R2 and R3 are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, -C(O)H, -(CH2)-COOR1, -(CH2)nSH,
-(CH2)nOH, -(CH2)nNH2, -(CH2)nOSO2, -(CH2)nCOH, - (CH2)nCOR1, -(CH2)nCONR1, -(CH2)nCOOH, - (CH2)nCH(X)(Y), H, Cl, Br, F, I and NO2;
wherein R1 is a linear or branched alkyl or aryl; n is 0 to 8; X is NH2; Y is COOH and wherein R2 to R3 can be protonated.
21. The ruthenium complex, use or composition according to any one of Claims 5 to 18 wherein B is selected from the group consisting of ethylene diamine, propylene diamine, 1,2-cyclohexane diamine and the corresponding alkylated amines thereof; 2,2'-bipyridine, 1,10-phenanthroline; 2-aminopicoline; potassium-bis-pyrazolyl borate, bis-pyrazolyl methane; and 1,2-bis(di-methylphosphino)ethane.
22. The ruthenium complex, use or composition according to any one of Claims 5 to 18 wherein B is represented by the general formula:
wherein R4 to R9 are the same or different and are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, -C(O)H, -(CH2)nCOOR', -(CH2)nSH, -(CH2)nOH, -(CH2)nNH2,
-(CH2)nOSO2, -(CH2)nCOH, -(CH2)nCOR1, - (CH2)nCONR1,
-(CH2)nCOOH, H, Cl, Br, F, I and NO2;
wherein R' is a linear or branched alkyl or aryl; n is 0 to 8; X is NH2; Y is COOH and wherein R4 to R9 can be protonated.
23. The ruthenium complex, use or composition according to any one of Claims 5 to 18 wherein M is represented by the general structure: 
wherein R10 is selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, -C(O)H, -(CH2)nCOOR1, -(CH2)nSH, -(CH2)nOH, -(CH2)nNH2,
-(CH2)nOSO2, -(CH2)nCOH, -(CH2)nCOR', - (CH2)nCONR1 ,
-(CH2)nCOOH, H, Cl, Br, F, I and N02;
wherein R1 is a linear or branched alkyl or aryl; n is 0 to 8; X is NH2; Y is COOH and wherein R10 can be protonated.
24. The ruthenium complex, use or composition according to any one of Claims 5 to 18 wherein T is selected from the group consisting of 2,2',6",2"-terpyridine, bis-(2- pyridylmethyl)amine, bis-(2-imidazolylmethyl)amine; potassium tris pyrazolyl borate; 1,4,7-triazacyclononane; and 1,4,7-trithiacyclononane.
25. The composition according to any one of Claims 16 to 24 further comprising an immunosuppressant selected from the group consisting of cyclosporin, rapamycin, FK-506, azathioprine, mizoribine, mycophenolate mofetil, brequinar sodium, leflunomide, 15-deoxyspergulin and combinations thereof.
26. The ruthenium complex or use according to any one of Claims 5 to 11, 13 to 15, 19 to 25 wherein the autoimmune disease is selected from the group consisting of graft rejection, insulin dependent diabetes mellitus, rheumatoid arthritis, psoriasis, hyperplasia of the epidermis, contact dermatitis and symptoms associated therewith, steroid resistant asthma, multiple sclerosis and lupus erythematosus.
27. A method for preventing or reducing a T-lymphocyte mediated immune response (e.g., autoimmune response) of a mammal, comprising administering to the mammal the ruthenium complex of Claim 1 or 4 or any claim appended thereto, or the composition according to any one of Claims 16 to 25.
28. The method of Claim 27 wherein the autoimmune disease is selected from the group consisting of graft rejection, insulin dependent diabetes mellitus, rheumatoid arthritis, psoriasis, hyperplasia of the epidermis, contact dermatitis and symptoms associated therewith, steroid resistant asthma, multiple sclerosis and lupus erythematosus .
29. A method for treating hyperproliferative vascular disorders in a mammal, comprising administering to the mammal the ruthenium complex of Claim 1 or 4 or any claim appended thereto, or the composition according to any one of Claims 16 to 25.
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 | 1994-10-28 | ||
| US08/331,388 US5512687A (en) | 1994-10-28 | 1994-10-28 | Compounds for inhibiting immune response |
| US47252595A | 1995-06-07 | 1995-06-07 | |
| US08/482,308 | 1995-06-07 | ||
| US08/472,525 | 1995-06-07 | ||
| US08/482,308 US5708022A (en) | 1994-10-28 | 1995-06-07 | Method for inhibiting immune response |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1996013510A1 true WO1996013510A1 (en) | 1996-05-09 |
Family
ID=27502438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1995/014067 WO1996013510A1 (en) | 1994-10-28 | 1995-10-30 | Ruthenium complexes and their use as immunosuppressive agents |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU4017695A (en) |
| WO (1) | WO1996013510A1 (en) |
Cited By (12)
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| 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 (en) * | 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 | Method for removing transition metals, particularly from metathesis products |
| WO2007089929A3 (en) * | 2006-01-31 | 2007-10-18 | Heller E & Co | Osmium compounds for treatment of psoriasis |
| US8216582B2 (en) | 2006-06-23 | 2012-07-10 | Alethia Biotherapeutics Inc. | Polynucleotides and polypeptide sequences involved in cancer |
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
| 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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| 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 |
| 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 |
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| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
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