# US 5,708,022 A · Method for inhibiting immune response

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- Number: US 5,708,022 A
- Document ID: US5708022A
- Status: Granted
- Kind: A
- Application number: 08/482,308
- Filed: 1995-06-07
- Granted: 1998-01-13
- Earliest claimed: 1994-10-28
- Assignees: Procept, Inc.
- Inventors: Cecilia M. Bastos; Timothy D. Ocain
- Web page: https://patentgrep.com/patent/US5708022A

## CPC

- C07F 15/0053: {without a metal-carbon linkage}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Use of ruthenium complexes as immunosuppressive agents to prevent or significantly reduce graft rejection in organ and bone marrow transplantation is 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.

## Claims

### Claim 1

A method of preventing or substantially reducing a T-lymphocyte mediated immune response associated with autoimmune disease in a mammal in need thereof comprising administering to a mammal, a ruthenium complex having the general formula:
›RuM.sub.m B.sub.b T.sub.t P.sub.p !Z
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, 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 m+b+t+p is 1, 2, 3, 4, 5 or 6;
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;
wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen containing ligands, sulfur containing ligands and phosphorus containing ligands; and
wherein when the complex is charged then Z is at least counterion of appropriate charge to render the overall charge of the complex neutral.

### Claim 2 (depends on 1)

The method of claim 1 wherein M is a nitrogen containing ligand selected from the group consisting of imidazole, picoline, pyridine, ammonia, triazole, pyrazole, quinoline, pyrazine, pyridazine, pyrimidine, quinoxaline, quinazoline, isoquinazoline, piperidine and their derivatives obtained by substituting for one or more hydrogen atoms with one or more of the following moieties C1-C5 alkyl, C2-C5 alkenyl, hydroxy, nitro, amino, carboxyl, ester, di-C1-C4 alkyl amine, phenyl, benzyl, imidazole and combinations thereof.

### Claim 3 (depends on 2)

The method of claim 2 wherein the imidazole has the general formula: ##STR4## where R.sup.2 and R.sup.3 are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, --C(O)H, --COOR.sup.1, --CONR.sup.1, --COOH, --CH.sub.2 NH.sub.2, --CH.sub.2 OSO.sub.2, --CH.sub.2 COH, --CH.sub.2 COR.sup.1, --CH.sub.2 CONR.sup.1, --CH.sub.2 COOH, H, Cl, Br, I and NO.sub.2 ; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 4 (depends on 1)

The method of claim 1 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.

### Claim 5 (depends on 1)

The method of claim 1 wherein B is represented by the general formula: ##STR5## wherein R.sup.4 to R.sup.9 are the same or different from each other and are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, --C(O)H, --COOR.sup.1, --CONR.sup.1, --COOH, --CH.sub.2 NH.sub.2, --CH.sub.2 OSO.sub.2, --CH.sub.2 COH, --CH.sub.2 COR.sup.1, --CH.sub.2 CONR.sup.1, --CH.sub.2 COOH, H, Cl, Br, I and NO.sub.2 ; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 6 (depends on 1)

The method of claim 1 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.

### Claim 7 (depends on 1)

The method of claim 1 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); .alpha.,.alpha.'-bis-(bis-(2-diphenylphosphino)ethyl)amino)ethane and .alpha.,.alpha.'-bis-(bis-(2-diphenylphosphino)m-xylene).

### Claim 8 (depends on 1)

The method of claim 1 wherein Z is a counterion selected from the group consisting of F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-, NO.sub.3.sup.-, NH.sub.4.sup.+, NR.sup.1.sub.4.sup.+, PF.sub.6.sup.-, BPh.sub.4.sup.-, ClO.sub.4.sup.-, S.sub.8.sup.-2, S.sub.2 O.sub.7.sup.-2, RuCl.sub.4.sup.-2, K.sup.+, SO.sub.4.sup.-2, Li.sup.+, Na.sup.+ and R.sup.1 ImH.sup.+, where Im is imidazole; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 9 (depends on 1)

The method of claim 1, further comprising administering the ruthenium complex with asteroid and/or an immunosuppressant selected from the group consisting of cyclosporin, rapamycin, FK-506, azathioprine, mizoribine, mycophenolate mofetil, brequinar sodium, leflunomide and 15-deoxyspergualin.

### Claim 10 (depends on 1)

The method of claim 1 wherein the complex selected from the group consisting of:
›RuCl(NH.sub.3).sub.5 !Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (4-MeIm)!Cl.sub.3 ;
cis-›RuCl.sub.2 (NM.sub.3)4!Cl;
trans-›Ru(SO.sub.4)(py)(NH.sub.3).sub.4 !Cl;
cis -Ru(DMSO).sub.4 Cl.sub.2 ;
›Ru(1-MeIm).sub.6 !Cl.sub.2 ;
›Ru(1-MeIm).sub.6 !(PF.sub.6).sub.3 ;
›Ru(1-MeIm).sub.6 !Cl.sub.3 ;
trans-›Ru(Im)(py)(NH.sub.3).sub.4 !Cl.sub.3 ;
cis-›Ru(Im).sub.2 (NH.sub.3).sub.4 !Cl.sub.3 ;
trans-›Ru(Im).sub.2 (NM.sub.3).sub.4 !Cl.sub.3 ;
trans-›Ru(Im)Cl(NH.sub.3).sub.4 !Cl.sub.2 ;
ImH›trans-Ru(Im).sub.2 Cl.sub.4 !;
trans-›RuCl.sub.2 (cyclam)!Cl;
trans-›Ru(SO.sub.4)(Im)(NH.sub.3).sub.4 !Cl;
K.sub.2 ›Ru(H.sub.2 O)Cl.sub.5 !;
›Ru(Im).sub.6 !Cl.sub.2 ;
trans-›Ru(1-MeIm).sub.4 Cl.sub.2 !Cl;
2-MeImH›trans-Ru(2-MeIm).sub.2 Cl.sub.4 !;
4-MelmH›trans-Ru(4-MeIm).sub.2 Cl.sub.4 !;
›Ru(4 -MeIm).sub.6 !Cl.sub.2 ;
›Ru(Im).sub.6 !Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (BzIm)!Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (Im)!Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (py)!(PF.sub.6).sub.2 ;
›Ru(NH.sub.3).sub.5 (py)!Cl(RuCl.sub.4);
›Ru(NH.sub.3).sub.6 !Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (L-his)!Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (4-MeIm-5-CHO)!Cl.sub.3 ;
trans-›Ru(NH.sub.3).sub.4 (py).sub.2 !(PF.sub.6).sub.2 ;
trans-›Ru(NH.sub.3).sub.4 (py).sub.2 !Cl.sub.3 ;
cis-›Ru(NH.sub.3).sub.4 (L-his).sub.2 !Cl.sub.3 ;
cis-›Ru(NH.sub.3).sub.4 (py).sub.2 !Cl.sub.3 ;
cis-›Ru(NH.sub.3).sub.4 (PPh.sub.3).sub.2 !Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (4 -pic)!Cl (RuCl.sub.4);
›Ru(NH.sub.3).sub.5 (4-pic)!Cl.sub.3 ;
cis-›Ru(NH.sub.3).sub.4 (1-MeIm).sub.2 !Cl.sub.3 ;
›Ru(en).sub.3 !Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (2-NH.sub.2 -5-Me-py)!Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (4 -NH.sub.2 -py)!Cl.sub.3 ;
cis-›Ru(NH.sub.3).sub.4 (4-pic).sub.2 !Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (PhCCH)!Cl.sub.2 ;
›Ru(NH.sub.3).sub.5 (4- CH.sub.2 CO.sub.2 H-py)!Cl.sub.3 ;
›Ru(NH.sub.3).sub.5 (3-.beta.-py-ala-OH)!Cl.sub.3 ; and
›Ru(NH.sub.3).sub.3 (Im).sub.3 !Cl.sub.3 ;
wherein Im is imidazole, py is pyridine, his is histidine, DMSO is dimethylsulfoxide, bipy is 2,2'-bipyridine, BzIm is benzimidazole, pic is picoline, phen is 1,10-phenanthroline, ala is alanine, cyclam is 1,4,8,11-tetracyclotetradecane, MeIm is methylimidazole, Ph is phenyl, and PPh is phenyl phosphine.

### Claim 11 (depends on 10)

The method of claim 10 wherein the autoimmune disease is selected from the group consisting of 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.

### Claim 12

A method of preventing or substantially reducing a T-lymphocyte mediated immune response associated with autoimmune disease in a mammal, comprising administering to the mammal a ruthenium complex having the general formula:
›(RuM.sub.m B.sub.b T.sub.t)-O-(RuM'.sub.m' B'.sub.b' T'.sub.t')!Z
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 m+b+t and m'+b'+t' are independently 2, 3 or 5;
wherein B and B' are independently 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 and T' are independently 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.

### Claim 13 (depends on 12)

The method of claim 12 wherein M and M' are independently a nitrogen containing ligand selected from the group consisting of imidazole, pyridine, ammonia, triazole, pyrazole, quinoline, pyrazine, pyridazine, picoline, pyrimidine, quinoxaline, quinazoline, isoquinazoline, piperidine and their derivatives obtained by substituting for one or more hydrogen atoms with one or more of the following moieties C1-C5 alkyl, C2-C5 alkenyl, hydroxy, nitro, amino, carboxyl, ester, di-C1-C4 alkyl amine, phenyl, benzyl, imidazole and combinations thereof.

### Claim 14 (depends on 13)

The method of claim 13 wherein the imidazole has the general formula: ##STR6## where R.sup.2 and R.sup.3 are independently selected from the groups consisting of aryl, heteroaryl, linear and branched alkyl, --C(O)H, --COOR.sup.1, --CONR.sup.1, --COOH, --CH.sub.2 NH.sub.2, --CH.sub.2 OSO.sub.2, --CH.sub.2 COH, --CH.sub.2 COR.sup.1, --CH.sub.2 CONR.sup.1, --CH.sub.2 COOH, H, Cl, Br, I and NO.sub.2 ; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 15 (depends on 12)

The method of claim 12 wherein B and B' are independently 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.

### Claim 16 (depends on 12)

The method of claim 12 wherein B and B' are independently represented by the general formula: ##STR7## wherein R.sup.4 to R.sup.9 are the same or different from each other and are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, --C(O)H, --COOR.sup.1, --CONR.sup.1, --COOH, --CH.sub.2 NH.sub.2, --CH.sub.2 OSO.sub.2, --CH.sub.2 COH, --CH.sub.2 COR.sup.1, --CH.sub.2 CONR.sup.1, --CH.sub.2 COOH, H, Cl, Br, I and NO.sub.2 ; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 17 (depends on 12)

The method of claim 12 wherein T and T' are independently 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.

### Claim 18 (depends on 12)

The method of claim 12 wherein Z is a counterion selected from the group consisting of F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-, SO.sub.4.sup.-2, NO.sub.3.sup.-, NH.sub.4.sup.+, NR.sup.1.sub.4.sup.+, PF.sub.6.sup.-, B{h.sub.4.sup.-, ClO.sub.4.sup.-, S.sub.8.sup.-2, S.sub.2 O.sub.7.sup.-2, RuCl.sub.4.sup.-2, K.sup.+, Li.sup.+, Na.sup.+ and R.sup.1 ImH.sup.+, where Im is imidazole; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 19

A method of preventing or substantially reducing a T-lymphocyte mediated immune response associated with autoimmune disease in a mammal in need thereof comprising administering to a mammal, a ruthenium complex having the general formula:
›(RuM.sub.m B.sub.b T.sub.t)--O--(RuM".sub.m" B".sub.b" T".sub.t")--O--(RuM'.sub.m' B'.sub.b' T'.sub.t')!Z
wherein Ru is ruthenium having an oxidation state of 2, 3 or 4;
wherein M, M' and M" are independently a mono-dentate 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 m+b+t and m'+b'+t' are independently 2, 3 or 5 and wherein m"+b"+t"is 2, 3 or 4;
wherein B, B' and B" are independently 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, T' and T" are independently 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.

### Claim 20 (depends on 19)

The method of claim 19 wherein M, M' and M" are independently a nitrogen containing ligand selected from the group consisting of imidazole, picoline, pyridine, ammonia, triazole, pyrazole, quinoline, pyrazine, pyridazine, pyrimidine, quinoxaline, quinazoline, isoquinazoline, piperidine and their derivatives obtained by substituting for one or more hydrogen atoms with one or more of the following moieties C1-C5 alkyl, C2-C5 alkenyl, hydroxy, nitro, amino, carboxyl, ester, di-C1-C4 alkyl amine, phenyl, benzyl, imidazole and combinations thereof.

### Claim 21 (depends on 20)

The method of claim 20 wherein the imidazole has the general formula: ##STR8## where R.sup.2 and R.sup.3 are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, --C(O)H, --COOR.sup.1, --CONR.sup.1, --COOH, --CH.sub.2 NH.sub.2, --CH.sub.2 OSO.sub.2, --CH.sub.2 COH, --CH.sub.2 COR.sup.1 , --CH.sub.2 CONR.sup.1, --CH.sub.2 COOH, H, Cl, Br, I and NO.sub.2 ; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 22 (depends on 20)

The method of claim 20 wherein B, B' and B" are independently 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-methyl-phosphino)ethane.

### Claim 23 (depends on 20)

The method of claim 20 wherein B, B' and B" are independently represented by the general formula: ##STR9## wherein R.sup.4 to R.sup.9 are the same or different from each other and are independently selected from the group consisting of aryl, heteroaryl, linear and branched alkyl, --C(O)H, --COOR.sup.1, --CONR.sup.1, --COOH, --CH.sub.2 NH.sub.2, --CH.sub.2 OSO.sub.2, --CH.sub.2 COH, --CH.sub.2 COR.sup.1, --CH.sub.2 CONR.sup.1, --CH.sub.2 COOH, H, Cl, Br, I and NO.sub.2 ; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 24 (depends on 20)

The method of claim 20 wherein T, T' and T" are selected from the group consisting of 2,2',6",2"-terpyridine, bis-(2-pyridyl)methylamine; bis-(2-imidazolylmethyl)amine; potassium tris pyrazolyl borate; 1,4,7-triazacyclononane; and 1,4,7-trithiacyclononane.

### Claim 25 (depends on 19)

The method of claim 19 wherein Z is a counterion selected from the group consisting of F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-, SO.sub.4.sup.-2, NO.sub.3.sup.-, NH.sub.4.sup.+, NR.sup.1.sub.4.sup.+, PF.sub.6.sup.-, BPh.sub.4.sup.-, ClO.sub.4.sup.-, S.sub.8.sup.-2, S.sub.2 O.sub.7.sup.-2, RuCl.sub.4.sup.-2, K.sup.+, Li.sup.+, Na.sup.+ and R.sup.1 ImH.sup.+, where Im is imidazole; wherein R.sup.1 is a linear or branched alkyl or aryl.

### Claim 26

A method for treating hyperproliferative vascular disorders comprising administering a ruthenium complex having the general formula:
›RuM.sub.m B.sub.b T.sub.t P.sub.p !Z
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, 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 m+b+t+p is 1, 2, 3, 4, 5 or 6;
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;
wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen 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.

### Claim 27

A method of preventing or substantially reducing a T-lymphocyte mediated immune response associated with graft rejection in a mammal in need thereof comprising administering to a mammal, a ruthenium complex having the general formula:
›RuM.sub.m B.sub.b T.sub.t P.sub.p !Z
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, 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 m+b+t+p is 1, 2, 3, 4, 5 or 6;
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;
wherein P is a polydentate ligand selected from the group consisting of nitrogen containing ligands, oxygen 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.

### Claim 28

A method of preventing or substantially reducing a T-lymphocyte mediated immune response associated with graft rejection in a mammal comprising administering to a mammal, a ruthenium complex having the general formula:
›Ru(Im).sub.6 !Cl.sub.2
wherein Im is imidazole.