Methods of preparing manganese complexes of nitrogen-containing macrocyclic ligands

• US 5,610,293 A
• Filed: 05/16/1995
• Issued: 03/11/1997
• Est. Priority Date: 07/19/1991
• Status: Expired due to Term

• Current Assignee: Pharmacia Corporation (Pfizer Inc.)
• Original Assignee: Monsanto Company (Bayer AG)
• Inventors: Modak, Anil S., Neuman, William L., Riley, Dennis P., Lennon, Patrick J., Weiss, Randy H., Aston, Karl W.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Sripada, Pavanaram K.
• Application Number:
  US08/442,455
• Time in Patent Office: 665 Days
• Field of Search: 540/474, 514/161, 514/183
• US Class Current: 540/474
• CPC Class Codes: C07D 259/00 Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

The present invention is directed to low molecular weight mimics of superoxide dismutase (SOD) represented by the formula: ##STR1## wherein R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ and X, Y, Z and n are as defined herein, useful as therapeutic agents for inflammatory disease states and disorders, ischemic/reperfusion injury, stroke, atherosclerosis, hypertension and all other conditions of oxidant-induced tissue damage or injury.

Claims

1. Method of making a compound represented by the formula ##STR7## wherein R is selected from the group consisting of alkyl having 2 to 22 carbon atoms, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl radicals comprising:

a) reducing an amino acid amide to produce the corresponding substituted ethylenediamine;

b) tosylating the diamine to produce the corresponding di-N-tosyl derivative;

c) reacting the di-N-tosyl derivative with a di-O-tosylated tris-N-tosylated triazaalkane diol to produce the corresponding substituted N-pentatosylpentaazacycloalkane;

d) removing the tosyl groups; and

e) recovering the resulting compound.

2. Method of claim 1 wherein said amino acid amide is represented by the formula:

##STR8## wherein R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl and aralkyl radicals.

3. A process for preparing a complex represented by the formula:

##STR9## wherein R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ independently are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or R₁ or R'"'"'₁ and R₂ or R'"'"'₂, R₃ or R'"'"'₃ and R₄ or R'"'"'₄, R₅ or R'"'"'₅ and R₆ or R'"'"'₆, R₇ or R'"'"'₇ and R₈ or R'"'"'₈, and R₉ or R'"'"'₉ and R or R'"'"' together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms;

or R or R'"'"' and R₁ or R'"'"'₁, R₂ or R'"'"'₂ and R₃ or R'"'"'₃, R₄ or R'"'"'₄ and R₅ or R'"'"'₅, R₆ or R'"'"'₆ and R₇ or R'"'"'₇, and R₈ or R'"'"'₈ and R₉ or R'"'"'₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇ and R'"'"'₇, R₈ and R'"'"'₈, and R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ together with a different one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂,R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof;

comprising;

(a) reacting a compound of the formula;

##STR10## with a manganese(II) compound under essentially anaerobic conditions to produce a complex wherein all "R" groups are hydrogen;

or

(b) reacting a compound of the formula;

##STR11## with a manganese(II) compound under essentially anaerobic conditions to produce a complex wherein R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ are hydrogen;

or

(c) reacting a compound of the formula;

##STR12## with a manganese(II) compound under essentially anaerobic conditions to produce a complex of wherein R, R'"'"', R₂, R'"'"'₂, R₄, R'"'"'₄, R₆, R'"'"'₆, R₈ and R'"'"'₈, are hydrogen;

or

(d) reacting a compound of the formula;

##STR13## with a manganese(II) compound under essentially anaerobic conditions to produce a complex wherein R₁, R'"'"'₁, R₈ and R'"'"'₈ are hydrogen;

or

(e) reacting a compound of the formula;

##STR14## with a manganese(II) compound under essentially anaerobic conditions to produce a complex wherein R₃, R'"'"'₃, R'"'"'₄, R'"'"'₅, R₆ and R'"'"'₆ are hydrogen.

4. A process for preparing a complex represented by the formula:

##STR15## wherein R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ independently are selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or R₁ or R'"'"'₁ and R₂ or R'"'"'₂, R₃ or R'"'"'₃ and R₄ or R'"'"'₄, R₅ or R'"'"'₅ and R₆ or R'"'"'₆, R₇ or R'"'"'₇ and R₈ or R'"'"'₈, and R₉ or R'"'"'₉ and R or R'"'"' together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms;

or R or R'"'"' and R₁ or R'"'"'₁, R₂ or R'"'"'₂ and R₃ or R'"'"'₃, R₄ or R'"'"'₅, and R₆ or R'"'"'₆, R₇ or R'"'"'₇, and R₈ or R'"'"'₈ and R₉ or R'"'"'₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇, and R'"'"'₇, R₈ and R'"'"'₈, and R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ together with a different one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkhe.teroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof;

wherein X, Y and Z are ligands independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, aryl, thiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryl dithiocarbarnate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins, or the corresponding anions thereof, or X, Y and Z are independently attached to one or more of the "R" groups and n is an integer from 0 to 3 comprising;

(a) reacting a compound of the formula;

##STR16## with hydrogen and a hydrogenation catalyst under conditions to produce a complex wherein R'"'"'₂ and R'"'"'₉ are hydrogen, R₂ and R₉ are alkyl and R'"'"' and R'"'"'₁ are absent.

5. Method of making a compound represented by the formula:

##STR17## wherein R, R'"'"', R₁, R'"'"'₁,R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ independently are selected from the group consisting of hydrogen and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloallcyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or R₁ or R'"'"'₁ and R₂ or R'"'"'₂, R₃ or R'"'"'₃ and R₄ or R'"'"'₄, R₅ or R'"'"'₅ and R₆ or R'"'"'₆, R₇ or R'"'"'₇ and R₈ or R'"'"'₈, and R₉ or R'"'"'₉ and R or R'"'"' together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms;

or R or R'"'"' and R₁ or R'"'"'₁, R₂ or R'"'"'₂ and R₃ or R'"'"'₃, R₄ or R'"'"'₄ and R₅ or R'"'"'₅, R₆ or R'"'"'₆ and R₇ or R'"'"'₇, and R₈ or R'"'"'₈ and R₉ or R'"'"'₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇ and R'"'"'₇, R₈ and R'"'"'₈, and R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ together with a different one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, R'"'"'₉ which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonyl, phosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof;

wherein at least one "R" group is not hydrogen or if one "R" group is methyl, at least one other "R" group is not hydrogen wherein R, R'"'"', R₂,R'"'"'₂,R₄,R'"'"'₄, R₈ and R'"'"'₈ are hydrogen comprising;

(a) cyclizing a linear pentapeptide or the corresponding salt to produce a cyclic pentapeptide, and

(b) reducing said cyclic pentapeptide.

6. Method of making a compound represented by the formula:

##STR18## wherein R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ independently are selected from the group consisting of hydrogen and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or R₁ or R'"'"'₁ and R₂ or R'"'"'₂, R₃ or R'"'"'₃ and R₄ or R'"'"'₄, R₅ or R'"'"'₅ and R₆ or R'"'"'₆, R₇ or R'"'"'₇ and R₈ or R'"'"'₈, and R₉ or R'"'"'₉ and R or R'"'"' together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms;

or R or R'"'"' and R₁ or R'"'"'₁, R₂ or R'"'"'₂ and R₃ or R'"'"'₃, R₄ or R'"'"'₄ and R₅ or R'"'"'₅, R₆ or R'"'"'₆ and R₇ or R'"'"'₇, and R₈ or R'"'"'₈ and R₉ or R'"'"'₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇ and R'"'"'₇, R₈ and R'"'"'₈, R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ together with a different one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, R'"'"'₉ which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonlylphosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof;

wherein at least one "R" group is not hydrogen or if one "R" group is methyl, at least one other "R" group is not hydrogen wherein R₁, R'"'"'₁, R'"'"'₂, R'"'"'₇, R₈ and R'"'"'₈ are hydrogen comprising;

(a) tosylating a triazaalkane to produce the corresponding tris(N-tosyl) derivative,

(b) treating said tris(N-tosyl) derivative with a suitable base to produce the corresponding disulfonamide anion,

(c) dialkylating said disulfonamide anion with a suitable electrophile to produce a derivative of a dicarboxylic acid,

(d) treating said derivative of a dicarboxylic acid to produce the corresponding dicarboxylic acid,

(e) treating said dicarboxylic acid to produce the corresponding diacid dichloride,

(f) reacting said diacid dichloride with a vicinal diamine in the presence of a base to produce the corresponding tris(tosyl) diamide macrocycle,

(g) removing the tosyl groups, and

(h) reducing the amides of said macrocycle.

7. Method of making a compound represented by the formula:

##STR19## wherein R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ independently are selected from the group consisting of hydrogen and alkyl alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or R₁ or R'"'"'₁ and R₂ or R'"'"'₂, R₃ or R'"'"'₃ and R₄ or R'"'"'₄, R₅ or R'"'"'₅ and R₆ or R'"'"'₆, R₇ or R'"'"'₇ and R₈ or R'"'"'₈, and R₉ or R'"'"'₉ and R or R'"'"' together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms;

or R or R'"'"' and R₁ or R'"'"'₁, R₂ or R'"'"'₂ and R₃ or R'"'"'₃, R₄ or R'"'"'₄ and R₅ or R'"'"'₅, R₆ or R'"'"'₆ and R₇ or R'"'"'₇, and R₈ or R'"'"'₈ and R₉ or R'"'"'₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇ and R'"'"'₇, R₈ and R'"'"'₈, R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ together with a different one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, R'"'"'₉ which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonlylphosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof;

wherein at least one "R" group is not hydrogen or if one "R" group is methyls at least one other "R" group is not hydrogen wherein R₃, R'"'"'₃, R'"'"'₄, R'"'"'₅, R₆ and R'"'"'₆ are hydrogen and R₄ and R₅ together with the carbon atoms they are attached to form a nitrogen containing heterocycle comprising;

(a) reacting a tetraaza compound containing two primary amine groups with dimethyl 2,6-pyridine dicarboxylate in methanol to produce a macrocycle which incorporates the pyridine ring as the 2,6-dicarboxamide,

(b) reducing the pyridine ring in said macrocycle to the corresponding piperidine ring, and

(c) reducing the amides of said macrocycle.

8. Method of making a compound represented by the formula;

##STR20## wherein R, R'"'"', R₁, R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ independently are selected from the group consisting of hydrogen and alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the α

-carbon of α

-amino acids;

or R₁ or R'"'"'₁ and R₂ or R'"'"'₂, R₃ or R'"'"'₃ and R₄ or R'"'"'₄, R₅ or R'"'"'₅ and R₆ or R'"'"'₆, R₇ or R'"'"'₇ and R₈ or R'"'"'₈, and R₉ or R'"'"'₉ and R or R'"'"' together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated ring structure having 3 to 20 carbon atoms;

or R or R'"'"' and R₁ or R'"'"'₁, R₂ or R'"'"'₂ and R₃ or R'"'"'₃, R₄ or R'"'"'₄ and R₅ or R'"'"'₅, R₆ or R'"'"'₆ and R₇ or R'"'"'₇, and R₈ or R'"'"'₈ and R₉ or R'"'"'₉ together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen in said formula, which nitrogen is also in the macrocycle and the R groups attached to the same carbon atoms of the macrocycle are absent;

R and R'"'"', R₁ and R'"'"'₁, R₂ and R'"'"'₂, R₃ and R'"'"'₃, R₄ and R'"'"'₄, R₅ and R'"'"'₅, R₆ and R'"'"'₆, R₇ and R'"'"'₇, R₈ and R'"'"'₈, R₉ and R'"'"'₉, together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms;

or one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, and R'"'"'₉ together with a different one of R, R'"'"', R₁, R'"'"'₁, R₂, R'"'"'₂, R₃, R'"'"'₃, R₄, R'"'"'₄, R₅, R'"'"'₅, R₆, R'"'"'₆, R₇, R'"'"'₇, R₈, R'"'"'₈, R₉, R'"'"'₉ which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula

space="preserve" listing-type="equation">(CH.sub.2).sub.x M(CH.sub.2).sub.w L(CH.sub.2).sub.z J(CH.sub.2).sub.y

wherein w, x, y and z independently are integers from 0 to 10, and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, thia, sulfonyl, sulfinyl, sulfonamide, phosphonlylphosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof;

wherein at least one "R" group is not hydrogen or if one "R" group is methyls at least one other "R" group is not hydrogen wherein R₁, R'"'"'₁, R'"'"'₂, R'"'"'₇, R₈ and R'"'"'₈ are hydrogen comprising;

(a) tosylating a triazaalkane to produce the corresponding tris(N-tosyl) derivative,

(b) treating said tris(N-tosyl) derivative with a suitable base to produce the corresponding disufonamide anion,

(c) reacting said disulfonamide artion with a bis(haloacetamide) of a vicinal diamine, prepared by reacting a vicinal diamine with an excess of haloacetyl halide in the presence of a base, to produce a substituted tris(N-tosyl) diamide macrocycle,

(d) removing the tosyl groups, and

(e) reducing the amides of said macrocycle.