MXPA98007449A - Complexes with iron of macrocyclic ligands containing nitrogen, effective as catalysts to dismute superox - Google Patents

Abstract

Superoxide-dismutated low molecular weight (SOD) mimics, represented by the formula: See figure wherein R, R1, R1, R1, R2, R2, R3, R3, R4, R4, R5, R5, R6, R6, R7, R7, R8, R8, R9 and R9 YX, Y, Z and n as defined herein, useful as therapeutic agents for inflammatory disease states and inflammatory disorders, ischemic / reperfusion damage, seizures, atherosclerosis, inflammable bowel disease and all other conditions of injury or tissue damage, induced by oxidation

Description

COMPLEXES WITH IRON OF MAC OCICLIC LIQUIDS CONTAINING NITROGEN. EFFECTS AS CATALYSTS TO DISMUNE SUPERQXIPQ REFERENCE TO RELATED REQUEST This application is a continuation in part of the application in serial form No. 08 / 397,469 »filed on March 1, 1995. which is a continuation of the application in process of the same cause, serial no. 08 / 231,599 »presented on April 22, 1994.

BACKGROUND OF THE INVENTION The present invention relates to compounds effective as cata lystors for dismuting superoxide and »more particularly» refers to complexes with iron (II) or iron (III) of macrocyclic ligands of fifteen »nitrogen containing» catalytically dismutating the superoxide. The application Serial No. 08 / 397,469 is incorporated herein by this reference "in its entirety. The enzyme superoxide do-dismutase catalyzes the conversion of superoxide to oxygen and hydrogen peroxide »according to equation (1): Oa - + Oa - + ZH + - > Oa + HaOa (1) (hereinafter referred to as dismutation). It is postulated that reactive oxygen metabolites, derived from superoxide, contribute to the pathology of tissues, in numerous inflammatory diseases and alterations, such as reperfusion injury to ischemic myocardium, inflammable bowel disease, rheumatoid arthritis, »osteoarthritis» atherosclerosis, hypertension, metastasis »psoriasis, rejection of organ transplantation, radiation induced damage, asthma, influenza, stroke, burns and trauma. eg, Bulkley, Q. B., Reactive oxy- metabolites and reperfusion in.?: aberrant triggering of reticuloendothelial function; The Lancet. volume 344 »pages 934-36» October 1, 1994; Grisham, M. B. »Oxidant and -free radicáis n inflammatory bowel disease. The Lancet »volume 344. pages 859-861, September 24, 1994; Croes »C. E. et al., Reactivating oxygen species and the lung, The Lancet. volume 344. pages 930-33 »October 1, 1994» Jenner. P. »Oxida ve damage in neurodegenerat e disease. The Lancet. volume 344. pages 796-798. September 17, 1994; Cerutti. P. A .. O? Y-ra icals and cancer, The Lancet, volume 344, pages 862-863, September 24, 1994; Simic, M. G. and co-authors, Oxygen Radicáis in Biology and Medicine. Basic Life Sciences, volume 49. Plenum Press, New York and London, 1988; We ss, J. Cell. Biochem., 1991, Suppl. 15C, 216 Abstract C110 (1991); Petkau A. Cancer Treat. Rev., 13, 17 < 1986); McCord, J. Free Radicáis Biol. Med., 2, 307 (1986); and Bannister, J. V. and coauthors, Crit. Rev. Biochem., 22, 111 (1987). The references identified above from The Lancet teach the nexus between free radicals, superoxide derivatives and a variety of diseases. In particular, the Bulkley and Grisham references specifically teach that there is a nexus between dismutation and superoxide and the final treatment of the disease. It is also known that superoxide is involved in the decomposition of muscle relaxant factor derived from the endothelium (EDRF). , by its designation in English: Endothelium-Derived vascular Relaxing Factor), which has been identified as nitric oxide (NO) and which the EDRF is protected against decomposition by the superoxide-dißm rate. This suggests a central role for the activated oxygen species »derived from superoxide. in the pathogenesis of vasospasm »thrombosis and atherosclerosis. See »for example» Gryglews i »R. J. and co-authors» Superox and Anion s involved in the Breakdown of Endothelium-derived Vascular Relaxing Factor. Nature volume 320. page 454-456 (1986) and Palmer »R. M. J. and co-authors Nitric Oxide Relay Accounts for the Biological! Activity of Endothelium Derived Relaxing Factor, Nature. Volume 327. pages 523-526 (1987). Clinical trials and animal studies with natural, recombinant and modified superoxide-d-smutase enzymes have been completed or are proceeding to demonstrate the therapeutic efficacy of reduced levels of superoxide in the disease states noted above.

However, numerous problems have arisen with the use of enzymes as potential therapeutic agents, including lack of oral activity, short half lives in vivo, immunogenicity with non-human derived enzymes, and maldistribution in the tissue. The iron complexes of the fifteen-member, nitrogen-containing macrocyclic ligands, which have low molecular weight replications of superoxide dismiutase (SOD), are useful as therapeutic agents and avoid many of the problems associated with SOD enzymes.

BRIEF DESCRIPTION OF THE INVENTION It is an object of the present invention to provide iron complexes of fifteen nitrogen containing macrocyclic ligands, which are low molecular weight mimics of superoxide dismutase (SOD), which are useful as therapeutic agents for inflammatory disease states. or inflammatory alterations, which are medicated, at least in part, by superoxide. It is another object of the invention to provide iron complexes of fifteen nitrogen-containing macrocyclic ligands that have unexpectedly improved stability compared to corresponding complexes with manganese.

According to the invention, "pharmaceutical compositions in unit dosage form" useful for dismutated delivery are provided. They comprise: (a) a therapeutically or prophylactically effective amount of an iron complex of the invention, and (b) a carrier. »Adjuvant or pharmaceutically acceptable vehicle» non-toxic. Also according to the invention a method is provided for preventing or treating a disease or disorder that is medicated "at least in part" by superoxide; which comprises administering to a subject in need of such prevention or treatment, a therapeutically or prophylactically effective amount of an iron complex of the invention.

DESCRIPTION PETFTl APA PE THE INVENTION The present invention is directed to iron complexes of fifteen nitrogen-containing macrocyclic ligands that catalyze the conversion of superoxide to oxygen and hydrogen peroxide. These complexes are represented by the formula: where R, R ', R »R'i.» Ra »R',» Ra «R'a» ^, R »Rβ» R'ß »Rß» 'ß »Rr» R't »Rß» R, «» R * and R '"are independently selected from the group consisting of hydrogen: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkyl, alkyl, cycloalkyl, cycloalkyl, cycloalkyl radical what, alkylocycloalkylene, cycloalkyl, heterocyclic, aryl and aralkyl, and radicals attached to the alpha carbon of alpha-amino acids; or Rx or ^ and Ra or R'JJ, R; »or Rta and R ^ or R» ^, Rß or R "ß and Rß o, ß» Rv »° R% ß ° Rrβ and R» ° R '» and R or Rf, together with the carbon atoms to which they are attached, independently form a saturated, partially saturated or unsaturated cyclic having from 3 to 20 carbon atoms, or R or Rt and R or R'A, and Ra or R'a, R3 or Rt3 and R ^ or R '^, RB or R'ß and R or R'ß, R ^ or R'., And Rß or R * ß and Rß or Rtβ. carbon atoms to which they are attached, independently form a heterocycle containing no nitrogen, having 2 to 20 carbon atoms, provided that when the nitrogen-containing heterocycle is an aromatic heterocycle that does not contain a bound hydrogen to nitrogen, the hydrogen bonded to the nitrogen that is shown in the above formula, nitrogen is also in the macrocyclic ligand or macrocyclic complex and the R groups attached to the same carbon atoms of the macrocycle are absent X. Y and Z represent ligands or charge neutralizing anions which are derived from any ligand or ligand system, monodentate or polylinated coordinator, or its corresponding anion (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). X, Y and Z are independently selected from the group consisting of halide, oxo »aquo, hydroxyl, alcohol» phenol »dioxygen» peroxo, hydrperoxo, alkyloxoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkylamino, heterocycline, lamino, amine oxides, hydrazine, alkylhydrazine »arylhydrazine» nitric oxide »cyanide. cyanate tioc anato. isocyanate. isothiocyanate »alkylnitrile. ari Ini tr lo »alquil i soni tri lo. arylisonitrile. nitrate, nitrite »azido» alkylsulfonic acid »alkylsulfonic acid» alkyl sulfoxide, aryl sulfoxide. alkylaryl sulfoxide, alkylsulfenic acid »arylsulfenic acid, alkylsulfonic acid, arylsulfinic acid, alkylthiolcarboxylic acid. arylthiolcarboxylic acid. alkylthiol thiocarboxylic acid. arylthiolthiocarboxylic acid, alkylcarboxylic acid (such as acetic acid, trifluoroacetic acid, oxalic acid), carboxylic acid (such as benzoic acid, phthalic acid), urea, alkyl urea, aryl urea, alkylarylurea, thiourea, alkylthiourea, arylthiourea, alkylaryl * thiourea, sulphate, sulphite, bisulfate, bisulphite, thiosulfate, thiosulphite, hydrosulfite, alkylphosphine, arylphosphine, alkylphosphine oxide, aluminum oxide, aluminum oxide, phosphine sulfur, arylphosphine sulfide, sulfur alkylarylphosphine, alkyl-phosphonic acid »aryphosphonic acid» alky1-phosphinoic acid »aric acid Ifosf» alkylphosphinous acid, aric acid Ifosfinoso, phosphate »thiophosphate» phosphite »pyrophosphite» triphosphate »phosphate acid» diacid phosphate »alky1 guanid »Ar guanidino» alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkylaryl carbamate, alkyl thiocarbamate, ar thiocarbamate, thio alkylaryl carbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryl dithiocarbamate »bicarbonate, carbonate, perchlorate» chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite »tetrahalomanganate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, hypophosphite, iodate. periodate, metaborate, tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate. ascorbate, saccharide, amino acid, hydroxamic acid, thiotosylate, and ion exchange resin anions, or systems in which one or more of X, Y, and Z are (are) independently linked to one or more of the groups " R ", where n is an integer of O or 1. The preferred ones of which selects X. Y and Z include: halide anions. organic acid and bicarbonate. As used herein, the term "alkyl", alone or in combination, means a straight-chain or branched-chain alkyl radical, containing from 1 to about 22 carbon atoms, preferably from about 1 to about 18. carbon atoms and, what is most preferred, around 1 to about 12 carbon atoms. Examples of such radicals include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, pentyl. isoamyl hexyl. octyl. nonyl decilo. dodecyl tetradecyl. hexadecyl octadecyl and eicosyl. The term "alkenyl", alone or in combination, means an alkyl radical having one or more double bonds Examples of such alkenyl radicals include, but are not limited to: ethenyl, propenyl, 1-butenyl, cis-2. -butenyl, trans-2-butenyl, isobuteleni, cis-2-pentenyl, trans-2-pentenyl, 3-methyl-1-butenyl, »2» 3-dimethyl-2-butenyl, 1-pentenyl-1-hexen 1-octenyl, decenyl, dodecenyl, tetradecenyl, hexadecyl, cis- and trans-9-octadecenyl, 1,3-? entadienyl, 2,4-pentadiene, 2,3-pentadienyl, 1,3-hexadienyl, 2,4- hexadieni 5.8.11,14-eicosatetraenyl and 9.12.15-octadecatrienyl The term "alkynyl" alone or in combination "means an alkyl radical having one or more triple bonds, examples of such alkynyl groups include but are not limitation to them: ethynyl »propynyl (propargyl)» 1-butynyl »1-octynyl, 9-octadecinyl or 1,3-pentadiinyl, 2,4-pentadiinyl, 1,3-heydoynyl and 2 »4-hexadiini lo. The term "cycloalkyl" "alone or in combination" means a cycloalkyl radical containing from 3 to about 10", preferably from 3 to about 8" and most preferred "from 3 to about 6" carbon atoms . Examples of said cycloalkyl radicals include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. cycloheptyl. cyclooctyl and per idronaphthyl. The term "cycloalkylalkyl" means an alkyl radical as defined above, which is substituted with a cycloalkyl radical as defined above. Examples of cycloalkylalkyl radicals include, but are not limited to: cyclohexylmethyl. cyclopenti Imeti lo »(4-isopropyl-cyclohexyl) methyl» (4-terbuti 1-cielohex 1) methyl »3-cyclohexypropyl. 2-Cyclohexylmethyl Ipentyl »3-cyclopentyl-methylhexyl» l- (4-neopentyl-l-cyclohexyl) -methylhexyl and l- (4-isopropyl-cyclohex-1) -methylheptyl. The term "cycloalkyl-cycloalkyl" means a cycloalkyl radical as defined above which is substituted with another cycloalkyl radical as defined above. Examples of cycloalkyl-cycloalkyl radicals include but are not limited to: cyclohexylcyclopentyl and cyclohexylcyclohexylo. The term "cycloalkenyl", alone or in combination, means a cycloalkyl radical having one or more double bonds. Examples of cycloalkenyl radicals include, but are not limited to: cyclopentenylo, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl and cyclooctadienyl. The term "cycloalkenylalkyl" means an alkyl radical as defined above, which is substituted with a cycloalkenyl radical as defined above. Examples of cycloalkenylalkyl radicals include, but are not limited to: 2-cyclohexen-1-ymethyl, 1-cyclopenten-1-ylmethyl, 2-d-cyclohexen-1-yl) ethyl, 3- (1-cyclopentenyl) 1-yl) -propyl, 1- (1-cyclohexen-1-ylmethyl) pentyl] -1- (1-cyclopenten-1-yl) hexyl. 6- (1-cyclohexen-1-yl) hexyl »1- (1-cyclopenten-1-yl) -nonyl and 1 - (1-c-clohexen-1-yl) noni lo. The terms "alkylcycloalkyl" and "alkenylcycloalkyl" mean a cycloalkyl radical as defined above which is substituted with an alkyl or alkenyl radical as defined above. Examples of alkylcycloalkyl and alkenyl cycloalkyl radicals include but are not limited to: 2-cyclobutyl. 1-methylcyclopentyl. 1-hexylcyclopentyl. 1-methylocyclohexy lo. 1- (9-octadecenyl) cyclopentyl and l- (9-octadeceni 1) cyclohexenyl. The terms "alkylcycloalkenyl" and "alkenyl cycloalkenyl" mean a cycloalkenyl radical or as defined above which is substituted with an alkyl or alkenyl radical. as defined above. Examples of alkylcycloalkenyl and alkenylcycloalkenyl radicals include, but are not limited to: 1-methyl 1-2-c-clopentyl-1-hexyl-2-cyclopentene or 1-ethyl-1-cyclohexenyl. l-butyl-2-cyclohexenyl »l- (9-octadecenyl) -2-cyclohexenyl and l- (2-pentenyl) -2-cyclohexeni lo. The term "aryl" "alone or in combination" means a phenyl or naphthyl radical optionally bearing one or more substituents selected from: alkyl, cycloalkyl, cycloalkene or, phenyl, naphthyl, heterocycle, alkoxy, alkaryl, alkoxy, halogen, hydroxy , amine, cyano, nitro, alkylthio, phenoxy, ether, trifluoromethyl and the like; such as phenyl, p-tolyl, 4-methoxyphene, 4- (terbutoxy) phenyl »4-fluorophenyl. 4-chlorophene, 4-hydroxyphene-1-1-naphthyl, 2-naphthyl and the like. The term "aralkyl", alone or in combination, means an alkyl or cycloalkyl radical as defined above, in which a hydrogen atom is replaced by an aryl radical as defined above, such as benzyl, 2-phenylethyl and lareß The term "heterocyclic" denotes ringstructures that contain at least one other class of atom, besides carbon, in the ring. The most common of the other kinds of atoms include: nitrogen, oxygen and sulfur. Examples of heterocyclics include, but are not limited to: pyrrolidinyl, piperidyl, imidazole, idinyl. tetrahydrofuryl. tetrahydrothieni lo. furyl, thienyl, pyridyl, quinolyl, ixoquinol, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl. triazolyl and tetrazolyl. The term "cyclic saturated, partially saturated or unsaturated" means fused ring structures in which 2 carbons of the ring are also part of the fifteen-member macrocyclic ligand. The annular structure may contain from 3 to 20 carbon atoms of R to 5 carbon atoms, and may also contain one or more other kinds of atoms, in addition to carbon. The most common of the other kinds of atoms include: nitrogen »oxygen and sulfur. The annular structure can also contain more than one ring. The term "nitrogen-containing heterocycle" means ring structures in which 2 carbons and one nitrogen in the ring are also part of the fifteen-member macrocyclic ligand. The ring structure may contain 2 to 20. preferably 4 to 10 carbon atoms; it may be partially or totally unsaturated or saturated »and may also contain nitrogen, oxygen and / or sulfur in the portion of the ring that is not part of the fifteen-member macrocyclic group. The term "organic acid anion" refers to carboxylic acid anions having from 1 to about 18 carbon atoms. The term "halide" means chloride or bromide. The total charge type of the complex can vary from negative to positive by carbon substitution of the appropriately charged groups in the macrocyclic framework. To consider the operative nature of the metallic iron center, the total charge in the complex can be adjusted as necessary to increase the desired pharmaceutical properties such as osmolarity, tissue distribution and non-target disposal. For example, if the solamene complex carries a neutral charge functionality, such as C-alkyl substitution, then the total charge in the complex will be determined by the iron center and will be positive. Multivalent complexes are available through the incorporation of dependent cations, such as the protonated aminoalkyl groups. These types of complexes can be linked to endogenous anions, anionic proteins, cell membranes and the like. If dependent anionic groups, such as carboxylates, phenolate, phosphonates, sulfonates and the like are bound, the total charge in the complex will be regarded as zero or positive, that is, an anionic complex will result. The dependent groups may be designed to axially chelate and displace axial limiting formations or may be designed specifically to not chelate, but to retain a type of charge. Currently the preferred compounds are those in which at least one, preferably at least two of the groups "R" represent alkyl, or alkyl substituted with -0R or or -NRxoRxx. wherein R.sup.o and R.sup.xx are independently hydrogen or alkyl, and the rest of the groups R represent hydrogen a saturated cyclic. partially saturated or unsaturated. or a nitrogen-containing heterocycle; even better. hydrogen or a saturated cyclic »partially saturated or unsaturated; those in which at least one. of rpeference at least two. of Rx or R 'and Ra or R »a. Ra or R », and R ^ or R ^. Rß or R'ß and Rß or RTß »R ° tt and ß ° R * s and R» ° R '»and R or Rt. Together with the carbon atoms to which they are attached» replenish a saturated cyclic »partially saturated or unsaturated, having 3 to 20 carbon atoms, and all remaining "R" groups are hydrogen, nitrogen containing heterocycle, alkyl or alkyl substituted with -0Rxo or -NRxoRxx groups; and those in which at least one "preferably at least two" of R or Rf »and Rx or R'x» Ra or R? a and R3 or Rt3 »R ^ or Rt ^ and Rβ or R'ß. Rß? R »ß R., or R"., And Rß or R'ß and R "or R '» »together with the carbon atoms to which they are attached» are bonded to form a nitrogen-containing heterocycle »which has 2 to 20 carbon atoms, and all remaining "R" groups are independently selected from "saturated cyclic" partially saturated or unsaturated "hydrogen" alkyl or alkyl substituted with -0Rxo or -NRxoRxx groups As used herein "groups" R "means all the R groups attached to the carbon atoms of the macrocycle" ie R »R '» Rx »R'» Ra. R "a» R3 » R * 3 »R ^" Rt "» Rβ »R'ß 'Ras' RT«' Rt 'RT-7 »Rsa» R'β' R »R, ß-Loe examples of complexes of the invention include» but without limitation to them »compounds that have the formulas: The macrocyclic ligand in which all R are H can be prepared according to the general synthesis scheme A "given below" using methods known in the art for the preparation of certain intermediates and certain ligands. See »for example» Richman and co-authors, J. Am. Chem. Soc., 96, 2268 (1974), Atkins and co-authors, Org. Synth , 58 »86 (1978); and EP 287,465. Thus, a triaza-alkane is tosylated in a suitable solvent system to produce the corresponding tris- (N-toßlo) derivative. Said derivative is then treated with a suitable base to produce the corresponding disulfonamide anion. The disulfonamide anion is then reacted with a di-N-tosylated diazaalkanediol di-O-tos to produce the corresponding pentatosa pentaazacycloalkane. The tosyl groups are then removed and the resulting compound is reacted with an iron compound under essentially anhydrous and anaerobic conditions to form the corresponding iron-pentaazacycloalkane complex. The macrocyclic ligands useful in the complexes of the present invention, wherein Rx. R'x »Ra» R'a. Rβ »R * ß 'ñ? T R," and R * ß can ßer H or any function as described above, can be prepared according to the general method of the peptides shown in Scheme B noted below. The process for preparing the cyclic peptide precursors of the linear peptides corresponding thereto are the methods known in the art, or significant modifications thereof. See, for example »Veber» D. F. and co-authors »J. Org. Chem., 44, 3101 (1979). The general method outlined in Scheme B that follows is an example that uses the sequential preparation in the solution phase of the linear pentapeptide running hoisted, from the N-terminus to the C-terminus. Alternatively, the reaction sequence for preparing the linear pentapeptide It can be carried out by solid phase preparation using concocted methods in this field. The reaction sequence from the C-terminus to the N-terminus could be conducted by convergent approaches, such as the coupling of the di- and tripeptides »when necessary. A) Yes. a Boc-protected amino acid is coupled to an amino acid ester, using common and current peptide coupling reagents. The new dipeptide Boc-ester is then saponified to the free acid, which is reconnected to another amino acid ester. The resulting tripeptide Boc-ester is again saponified and this method is continued until the free acid of the Boc-protected pentapeptide has been prepared. The Boc protecting group is removed under normal conditions and the resulting pentapeptide or its salt is converted to the cyclic pentapeptide. The cyclic pentapeptide is then reduced to pentaazacyclopentadecane with lithium aluminum hydride or borane. The final ligand is then reacted with an iron compound under essentially anaerobic conditions to form the corresponding pentaazacyclopentadecane complex with iron. The R groups in the macrocycles produced by the cyclic peptide pathway, ie. Rx, R'x, Ra, R'a, Rß »'B' R ^, t7, R9 and R'ß could be derived from the D or L forms of the amino acids alanine, aspartic acid, arginine, asparagine» cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine »lysine, methionine, proline, phenylalanine, serine, tryptophan, threonine, tyrosine, valine and / or R groups of non-natural alpha-amino acids, such as alkyl, ethyl, butyl , terbutyl, cycloalkyl, phenyl, alkenyl, allyl. alkynyl »aryl» heteroaryl »polycycloalkyl» polycycloalkyl »polycycloheteroaryl» imines, aminoalkyl, hydroxyalkyl, hydroxyl, phenol, amine oxides, thioalkyl, carboalkoxyalkyl, carboxylic acids and their derivatives, keto, ether, aldehyde, amine »nitrile» halogen »thiol» sulfoxide »sulfone, sulfonic acid» sulfur »disulfide» phosphonic acid »phosphinic acid» phosphine oxides »sulfonamides» amides »amino acids» peptide »proteins» carbohydrates »acids nucleic acids »fatty acids» lipids, nitro, hydroxylamines, radioactive acids, thiocarboni, borates, boranes, boraza »sil i lo» si loxi. if laza and its combinations. The macrocyclic ligands useful in the complexes of the present invention can also be prepared by the diacid dichloride route, shown in Scheme C below. Thus, it is possible to carry out a triazole in a suitable solvent system to produce the corresponding tris (N-to-yl) derivative. This derivative is treated with a suitable base to produce the corresponding disulfonamide anion. The disulfonamide anion is dialkylated with a suitable electrophile to produce a derivative of a dicarboxylic acid. This derivative of a dicarboxylic acid is treated to produce the dicarboxylic acid, which is then treated with a suitable reagent to form the diacid dichloride. The desired vicinal diamine is obtained in any of several ways. A way that is useful in the preparation of an aldehyde by reaction with cyanide in the presence of ammonium chloride, followed by acid treatment to produce the alpha-ammonium nitrile. The latter compound is reduced in the presence of acid and then treated with a suitable base to produce the vicinal diamine. The condensation of the diacid dichloride with the vicinal diamine, in the presence of a suitable base, forms the macrocyclic triphosid diamine. The tosyl groups are removed and the amides are reduced, and the resulting compound is reacted with an iron compound, under essentially anhydrous and anaerobic conditions, to form the suitably iron / pentaazacycloalkane / iron complex. The vicinal diamines had been prepared by the route shown (known as the Strecker synthesis) and ß acquired the vicinal diamines when commercially available. Any method of preparation of vicinal diamine could be used. It is also possible to prepare the macrocyclic ligands useful in the complexes of the present invention by the route of the bis (haloacetamide) shown in scheme D indicated below. Thus, a triazaalkane is tosylated in a suitable solvent system to produce the corresponding tris (N-tosyl) derivative. This derivative is treated with a suitable base to produce the corresponding disulfonamide anion. A bis (haloacetamide), for example, a bis-cycloacetamide, is prepared by a vicinal diamine, by reaction of the diamine with an excess of the haloacetyl halide, for example, chloroacetyl chloride, in the presence of a base. The disulfonamide anion of triß (N-toyl) triazaalkane is then reacted with the bis (chloroacetamide) of the diamine to produce the macrocycle triß (N-to 1i) d substituted amide. The tosyl groups are removed and the amides are reduced and the resulting compound is reacted with an iron compound, under essentially anhydrous and anaerobic conditions, to form the substituted pentaazacic or iron / iron complex, correspondingly. The most useful ligands in the complexes of the present invention, wherein R, R'x »R», R'a are part of an annular system of cis- or trans-cycloalkyl and Rß, R'B »Rt 'R * t and Rw' R 'can be H or any functionality previously described, can be prepared according to the pseudo-peptide method, shown in scheme E indicated below. A cy-1, 2-diamino-cycloalkane or a trans- (R, R) -l, 2-diaminocycloalkane or trans- (S, S) -l, 2-diaminocycloalkane, in combination with any amino acids. This allows the relative stereochemistry of the molten ring of cycloalkane and the substituents, Rß, R'ß »« »R, Rβ, Rf" »functional and stereochemical which are to be defined in any way. As an example, trans- (R, R) -l, 2-diaminocyclohexane onotosyl and is reacted with Boc anhydride to give the N-tosyl derivative, N-boc differentiated. Sulfonamide was rented with methyl bromoacetate using sodium hydride as the base and saponified to the free acid. The cyclohexanediamine containing N-toßi Iglina serves as a dipeptide surrogate in peptide synthesis in the solution phase, common and current. Thus, coupling with the amino acid ester functionality produces the corresponding pseudo-tripeptide. Doß divisions with TFA-sequential couplings produce the pseudo-pentapepti or that can be deprotected at the N-terminus and at the C-terminus, in one step, using HCl / AcOH. DPPA-mediated cyclization, followed by L AlH ^ or reduction with borane, produces the corresponding macrocyclic ligand. This ligand system is reacted with an iron compound, such as iron (III) chloride, essentially under anaerobic conditions, to form the corresponding functionalized iron complex (IID / pentaazacycloalkane.) Macrocyclic ligands, useful in complexes of the present invention, wherein Rx, R'x, Ra, R * a and RB, R'ß »Rβ» R, «» 80n are part of a cis- or trans-cycloalkyl ring system and Rß. ñ7w can ßer H or any previously described functional function can be prepared according to the iterative pseudo-peptide method, shown in Scheme F, below: A cis-1,2-diaminocycloalkane or a trans- (R »R) can be used. ) -l »2-diaminocycloalkane or trans- (SS) -l» 2-diaminocycloalkane in any combination with each other using this method and in combination with any amino acids.This allows the relative stereochemistry of both molten cycloalkane anions and of the substituents »Rß. R'ß» f uncional dad and stereochemistry that are going to be defined in any way. Thus »the dipeptide (S.S) -l» 2-diaminocyclohexyl-N-to-phenylglycine subrogated, prepared from (S.S) -1.2-diaminocyclohexane. exactly as in Scheme E, in the case of (R, R) -l, 2-diaminocyclohexane, it can be coupled with a functionalized amino acid ester, to give the corresponding pseudo-tripeptide. Division with TFA produces the TFA salt of the pseudo-tripeptide which is coupled with (R.R) -diaminocyclohexyl-N-toysilgl icine. The ßaponification and division with TFA produce the pseudo-pentapeptide that contains biß-cyclohexane. The separation mediated with DPPA, followed by reduction with lithium aluminum hydride or with borane produces the corresponding macrocyclic ligand fused to bis-cyclohexane. This ligand system is reacted with an iron compound, such as iron (III) chloride, essentially under anaerobic conditions to form the functionalized, correlated, iron (III) -pentazazacycloalkane complex. The macrocyclic ligands, useful in the complexes of the present invention, can also be prepared according to the general procedure shown in Scheme G noted below. Thus, an amino acid amide, which is the corresponding amide derivative, of an alpha-amino acid occurring in nature or not occurring in nature, is reduced to form the corresponding substituted ethylene diamine. Said amino acid amide may be the amide derivative of any of the many well-known amino acids. Preferred amino acid amides are those that are represented by the formula: where R eß such as ße previously defined. The most preferred are those in which R represents hydrogen, alkyl, cycloalkylalkyl and aralkyl radicals. The diamine is then cured to produce the di-N-tosyl derivative, which is reacted with a triazoalkanediol di-O-tisilated, tris-N-toß side, to produce the corresponding substituted N-pentatozai or substituted pentaazacic. The tosyl groups are then removed and the resulting compound is reacted with an iron compound under essentially anhydrous and anaerobic conditions to form the corresponding substituted iron-pentaazacycloalkane complex. The complexes of the present invention, in which R Rae 80n alkyl, and Ra, R'g ,, R ^, R * ^, Rβ »R'ß 'Rβ' R '*' R- * 'R't' R« R, «may be alkyl, arylalkyl or cycloalkylalkyl and R or Rf and R or R ', together with the carbon atoms to which they are attached, are bonded to form a nitrogen-containing heterocycle, can also be prepared according to the general procedure shown in the outlined H scheme below, using methods known in the art for the preparation of the iron-pentaazabicycloC12.3.1 * loctadectane precursor. see, for example, Ale? ander and coauthors, Inorg. Nucí Chem. Lett., 6, 445 (1970). Aßí »Æs condenses a 2» 6-diketopyridine with triethyltrantramine in the presence of an iron component to produce the iron-pentaazabicycloC12.3.13octa-dectane complex. The iron-pentaazabicycloC12.3.13octadectane complex with 5% rhodium on carbon is hydrogenated at a pressure of 70.3 kg / cm ** to give the corresponding iron-pentaazabicic1 or C12.3.1. Doctadecatriene complex. The macrocyclic ligands useful in the complexes of the present invention can also be prepared by the pyridinodiamide route. shown in Scheme I. as indicated below. A) Yes. a polyamine is condensed. such as a tetraaza compound containing two primary amine β, with dicarboxylate dimethyl 1-2.6-pyridine. heating in an appropriate solvent, for example, methanol. to produce a macrocycle incorporating the pyridine ring, such as 2,6-di carboxyamide. The pyridine ring in the macrocycle ß reduces the corresponding piperidine ring in the macrocycle, and then the amide β is reduced and the resulting compound is reacted with a compound, under essentially anhydrous and anaerobic conditions, to form the pentaazacycloalkane complex. replaced iron correßpondiente. When charge-neutralizing ligands or anions, ie, X, Y and Z are anions or ligands that can not be introduced directly into the compound and iron, the complex can be formed with those anions or ligands by carrying out a reaction of exchange with a complex that has been prepared by reacting the macrocycle with a compound of error.

ESPUHft A IHiOM SCHEME B BSPÜEM & B (OOMTIMQaCIO) NaOH, HfO CH3OH FA.CH?CI|ß HC véter SCHEME D 1 **, OCH, HCVHOAc «• F Rf, * o fl N HRR., 3.BIoe SCHEME E i (XSpOK? CLCK) UAIH 08Ht SCHEME F SCHEME F (CX »TD« BCI0N) UAIH4T «BHj H The pentaazamacrocycles of the present invention may possess one or more asymmetric carbon atoms and. in such a manner »are able to exist in the form of optical isomers» as well as in the form of racemic or non-racemic mixtures thereof. Optical isomers can be obtained by resolution of the racemic mixtures according to conventional methods "for example" by formation of the diastereomeric salts "by treatment with an optically active acid. Examples of suitable acids are tartaric acid »diaceti-1-tartaric» dibenzoyl-1-tartaric acid »di-toluoyl-1-tartaric acid and camphor-sulfonic acid» and then by separation of the mixture of diastereomers by crystallization followed by release of optically active beta-base ™ from de esaß sales. A different procedure for the separation of optical isomers involves the use of a chiral chromatography column. optimally selected to maximize the separation of enantiomers. Another additional available method involves the synthesis of covalent diastereoisomeric molecules. reacting one or more secondary amine groups of the compounds of the invention, with an optically pure acid in an activated form or an optically pure isocyanate. It is possible to separate the diastereomers synthesized by conventional means. such as chromatography »distillation, crystallization or sublimation; and then they can be hydrolyzed to give the enantio purely pure ligand. Likewise, the optically active compounds of the invention can be obtained using optically active starting materials, such as natural amino acids. The compounds or complexes of the present invention can be used to treat numerous inflammatory disease states and disorders that are mediated, at least in part, by superoxide. For example, damage by reperfusion to an ischemic organ, for example, reperfusion injury to the ischemic myocardium, surgically induced ischemia, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriasis, organ transplant rejections, radiation induced damage, tissue damage and injury, induced by oxidant; atherosclerosis, thrombosis, platelet accumulation, metastasis, stroke, acute pancreatitis, diabetes mellitus dependent on inßulin, disseminated intravascular coagulation, fat embolism, respiratory distress in adults and children, and carcinogenesis. The activity of the compounds or complexes of the present invention can be demonstrated to catalyze the dismutation of the superoxide utilizing the detached flow kinetic analysis technique that was described in Riley. D. P .. Rivers »W. J and Weiss, R. H.» Stopped-Flo Kinetic Analysis for Monitoring Superoxide Decav in Aqueous Systems, Anal. Biochem., 196, 344-349 (1991), which is incorporated herein by this reference. The kinetic analysis of stopped flow is a precise and direct method to quantitatively monitor the speed of decomposition of superoxide in water. The arrested flow kinetic analysis is suitable for selecting compounds for SOD activity and the activity of the complexes or complexes of the present invention, as shown by the detained flow analysis, correlate with the treatment of disease states and alterations indicated above. The total daily dose administered to a host in a single dose or in divided doses may be in amounts, for example, of about 1 to 100 mg / Kg of body weight daily, and more commonly, about 3 to 30 mg / kg. The dose unit compositions may contain quantities of submultiples of them, which constitute the daily dose. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the recipient treated and the particular mode of administration. The dose regimen for treating a disease condition with the compound and / or the composition of this invention is selected according to a variety of factors, including type, age, weight, sex, diet and medical condition. of the patient the severity of the disease, the route of administration; pharmacological considerations such as the activity, efficacy, pharmacokinetics and etogy profiles of the particular compound employed, whether a drug delivery system is used or the compound is administered as part of a drug combination. Thus, the dose regimen employed can actually vary within wide limits and, therefore, can be set apart from the preferred dose regimen noted above. The compounds of the present invention can be administered orally, parenterally, by spraying for inhalation, rectally or topically, in doßis unit formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles, non-toxic, conventional or non-toxic. , that is desired. Topical administration may also involve the use of transdermal administration, such as transdermal or ß-ß-toforeßis patches. The term "parenteral," as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal or nfusion techniques. The injectable preparations, for example, sterile, injectable aqueous or oleaginous suspensions, can be formulated according to the known art, using suitable dispersing or wetting agents and suitable suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension, in a diluent or solvent not to be used. co, parenterally acceptable, for example, as a solution in 1,3-butanediol.

Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, sterile oils are conventionally used as a solvent or suspension medium. For this purpose, any fixed soft oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables. Suppositories can be prepared for rectal administration of the drug by mixing the drug with a non-irritating excipient, such as cocoa butter and po ethylene glycols, which are solid at ordinary temperatures, but liquid at rectal temperature and, therefore, fuse in the rectum. and they release the drug. The solid dosage forms for oral administration may include capsules, tablets, pills, pores, granules and gels. In said solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. These dosage forms may also comprise, as in normal practice, additional substances other than interteß diluents, for example, lubricating agents, such as magnesium stearate. In the case of capsules, tablets and pills, the doßis forms may also comprise regulatory agents. Laß tablets and laß pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents commonly used in the art, such as water. Said compositions may also comprise adjuvants such as wetting agents, emulsifiers and susßpension agents, as well as sweetening, flavoring and perfuming agents. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds known to be effective against the specific disease condition which is the target of the treatment. The equivalents contemplated in the general formulas given above for the compounds and derivatives, as well as the intermediates, are compounds that correspond to them, and that have the same general properties, as well as the principal agents of the compásßtoß and such as laß wherein one or more of the various groups R are simple variations of the substituents as defined herein; for example, where R is an alkyl group higher than that indicated, or where the tosyl groups are other nitrogen or oxygen protecting groups; or wherein O-tosyl is a halide. Anions having a charge other than 1, for example, carbonate, phosphate and acid phosphate, can be used in place of the anions having a charge of 1 |. as long as they do not adversely affect the general activity of the complex. However, the use of anions that have a different charge of 1 will result in a slight modification of the general formula for the complex indicated above. Further, when a substituent is designated as, or may be, a hydrogen, the chemical nature e ?acta of a substituent that is different from hydrogen at that position, for example, a hydrocarbyl radical or a halogen or a hydroxy, amino group or similar functional group "not critical" as long as it does not adversely affect the general activity and / or the synthesis procedure. Additionally, it is contemplated that the iron (III) complexes are equivalent to the iron (III) complexes herein. The chemical reactions described above are described, in general, in terms of their widest application for the preparation of the compounds of this invention. Occasionally the reactions may not be wired as described for each compound included within the scope described. The compounds for which this will occur will be readily recognized by those skilled in the art. In all those cases, whether the reactions are successfully carried out by conventional modifications known to those skilled in the art, for example, by adequate protection of interfering groups, switching to alternative conventional reagents, by routine modification of the reaction conditions and the like, or other reactions described herein, or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all methods of preparation, all the starting materials are known or are easily prepared from known starting materials. Without further complication, it is believed that one of skill in the art can utilize the present invention to its fullest extent, by use of the foregoing description. Therefore, the following specific preferred modalities should be considered, simply as illustrative and not as a limitation of the rest of the description, absolutely not at all.

£ J £ M £ LJ23.

All reactants were used as they were received without purification, unless otherwise indicated. All of the NMR spectra were obtained on the Varian VXR-400 and VXR-400 nuclear magnetic resonance spectrometer. Qualitative and quantitative mass spectroscopy was performed on a Finnigan MAT90 »an FI? LIGAn 4500 and a Vß40-250T, using alcohol m-nitrobenzyl (NBA) or alcohol-nitrobenzyl co / LiCl (NBA-Li). Melting points (p.f.) are not corrected. The following abbreviations that refer to the amino acids and their protective groups are in accordance with the recommendations of the IUPAC-IUB. Commission on the Biochemical Nomenclature (Biochemistry, 11, 1726 (1972)) »and the common use. A Allaa L-alanine DAla D-alan na Gly glycine Ppg Propargi 1g1 i ci na Tyr L-ti rosin B Bzzll benzyl Boc terbutoxycarbonyl Et ethyl TFA trifluoroacetate DMF dimeti 1 formamide HOBT-H ^ O l-hydro? I monohydrate (lH) -benzotriazole EDC-HCl l- (3-d meti lami opropyl) -3- eti lcarbodi imide TEA triethylamine DMSO dimethyl sulfoxide T THHFF tetrahydrofuran DPPA azide diphenyl phosphoryl DMPU dimeti 1propi lenurea C concentration »g / cc DME 1,2-dimethoxy ethane . The abbreviation Cyc represents l »2-diclohe? Anodialym (the stereochemistry »ie» R R or S S »is indicated as such). Eßto allows a three-letter key peptide nomenclature to be used in the pseudopeptides containing the "residue" 1,2-cyclohexanediamine.

EXAMPLE 1 A.- Synthesis of l, 4,7-tris- (p-toluene sulfonyl 19-1,4,7-triazaheptane This compound was synthesized following the procedure of Atkins, TJ, Richman, JE, and Oettle. "F .; Synth. »5B» B6-9B (1978) To a stirred solution of 618 g »3.24 moles, of p-to-uensulfonyl chloride in 1500 ml of pyridine, at 0 ° C, a solution of 95.5 g was added, 0.926 moles of 1,4,7-triazaheptane in 150 ml of pyridine, under a dry argon atmosphere, keeping at a temperature of <50 ° C. Addition required 30 minutes, then let the mixture cool to room temperature , slowly, while stirring for 3 hours, "slowly added 2 liter of water to the cooled mixture (ice bath), the white precipitate formed was filtered and washed thoroughly with water, the pale yellow solid was dissolved in 3 liters of water. DMF and 4 liters of 0.1 N HCl were slowly added at 5 ° C. The suspension was filtered and the pale yellow solid was washed thoroughly with water and dried under vacuum to give 486 g (93X yield) of the product, e.g. F. 1B0-181 ° C; NMR with * H (DMSO-dw) delta 2.39 (S. 3 H), 2.40 (S. 6 H), 2.84 (m, 4 H); 3.04 (t, J = 6.9 Hz, 4 H); 7.40 (Cl, J = 8.1 HZ, 4 H), 7.59 (d.J = 8.3 Hz. 2 H), 7.67 (m..6 H).

B. Synthesis of the 1,7-diisode salt of 1,4,7-triß (p-toluenesulfonyl) -1,4,7-riazaheptane This was synthesized in accordance with the procedure of Atkinβ, T. J .; Richman, J. E and Oettle,. F.; Gold. Synth. , 58, B6-9B (197B). To a mechanically stirred suspension of 486 g, 0.859 mol, l, 4 »7-tris (p-toluenesulfonyl) -1,4-triazaheptane, prepared as in Example IA, in 1150 ml of ethanol, heated to low reflux argon atmosphere, a solution of sodium ethoxide (prepared by dissolving 39.5 g, 1.72 moles, of metallic sodium in 1.0 liter of absolute ethanol, as quickly as possible) was added to the room at room temperature, the clear brown solution which was formed rapidly, and add 1.0 liter of ethyl ether co.The crystals were filtered under argon blanket, washed with 3: 1 ethanol: ethyl ether and with ethyl ether, then loe crißtaleß was dried under vacuum to give 509 g ( 97X yield) of the product, as a white powder, NMR with AH (DMSO-dβ) delta 2.30 (8. 6 H), 2.36 (8. 3 H), 2.63 (t, J «8.7 HZ, 4 H), 2.B9 (t, J = 7.2 Hz »4 H), 7.11 (d, J = 8.1 Hz, 4 H), 7.28 (d, J = 8.0, 2 H), 7.46 (m, 6 H).

C. Synthesis of 1,8-i-p-toluene sulfonate of 3.6-bis (p-toluene-sulfone 1) -3,6-diazaoctane To a stirred solution of 566 g. 2.97 moles, of p-toluenesulfonyl chloride and 300 g. 2.97 moles, of triethylamine in 2.0 liters of methylene chloride at 0 ° C, under a dry argon atmosphere, added 100 g »0.675 mol» of 3,6-diazaoctane-l-diol in portion, keeping the temperature below 10 ° C. The addition required 30 minutes. The mixture was allowed to warm to room temperature while stirring for an additional 18 hours and then poured onto 1,000 g of ice. The methylene chloride layer was separated and washed with 10% HCl with water and with saturated NaCl solution and dried over magnesium sulfate. The solution was concentrated in vacuo at a volume of 1.5 liters. Crystallization by addition of 4 liters of hexane gave 477 g (yield 92X) of the product »as colorless needles, m.p. 151-153 ° C. NMR with - "- H (CDC13) delta 2.43 (s, 12 H), 3.29 (s, 4 H), 3.36 ítt J - 5.2 HZ, 4 H) 4.14 (t, J = 5.2 Hz, 4 H). 7.33 (d.J 7.8 HZ, 8 H), 7.71 (d, J = 8.2 Hz, 4 H), 7.70 (d, J = 8.3 Hz »4 H).

D. Synthesis of l, 4,7,10, l3-penta (p-toluene sulfonyl 1) -1,4,7,10,13-pentaazacyclopentadecane. This compound was synthesized following the procedure of Richman, J. E and Atkins, T. J., J. Am. Chem.

Soc., 96, 2268-70 (1974). To a stirred solution of the 1,7-diisodate salt of l.4.7-tris (p-toluenesulfonyl) -l, 4.7-triazaheptane »prepared as in Example IB (146 g» 0.240 moleß) in 2250 ml of anhydrous DMF , a solution of 185 g, 0.240 mol, of 1,8-di-p-tol-uensulfonate of 3,6-bis (p-toluenesulfoni 1) -3,6-diazaoctane prepared by drops was added dropwise over 3 hours. as in the example IC, in 1.020 ml of anhydrous DMF, under a dry argon atmosphere, maintaining the temperature at 100 ° C. After stirring for another hour at 100 °, the solution was concentrated in vacuo to a volume of 1.5 liter. 500 ml of water at 80 ° C was slowly added to crystallize the product. The resulting suspension was cooled slowly to 0 ° C and an additional 1.250 ml of water was added. The solid was filtered, washed thoroughly with water and then 90% ethanol and dried in vacuo. The matte white solid was dissolved in methylene chloride, the undesirable impurities were filtered off and the filtrate was washed with water and then dried in magnesium sulfate. The solvent was removed in vacuo to give a yellow solid which was purified by recrystallization from methylene-hexane chloride to give 164 g (69% yield) of the product, as a white crystalline solid, m.p. 290-293 ° C. NMR with -MHI (CDC1.,) Delta 2.44 (s, 15 H). 3.27 (8, 20 H), 7.32 (d, J = 8.3 HZ, 10 H), 7.66 (d, J - 8.3 Hz, 10 H).

E. Synthesis of 1,4,7,10,13-pentgazacyclopentadecane A mixture of 168 g, 0.170 mol, of 1.4, 7 was heated at 100 ° C, with stirring, under a dry argon atmosphere for 70 hours. , 10,13-penta (P-to1uensulfon 1) -l, 4, 7,10 »13-pentaazacyclopentadecane, prepared as in example ID, and 500 ml of concentrated sulfuric acid. To the resulting dark brown solution was added dropwise 500 ml of ethanol, with stirring, at 0 ° C, followed by 3 liters of ethyl ether. The white solid was filtered and washed with ethyl ether. The solid was then dissolved in 500 ml of water and the resulting solution was washed with ethyl ether. By reducing the volume of the solution in vacuo to 200 ml, the pH was adjusted to 10-11 with 10 N NaOH, and the solvent was removed in vacuo. Then 500 ml of ethanol was added and the vacuum removed under dry conditions. The oily, cinnamon solids were extracted with 2 x 500 ml of hot THF and filtered at room temperature. The filtrate was combined and the solvent was removed in vacuo to give the crude product as a yellow crystalline solid, which was then digested back into acetonitrile and filtered to remove the insoluble impurities. Recrystallization from cold acetonitrile (-20 ° C) gave 11.3 g (31% yield) of the product, as colorless needles, m.p. 108-109 ° C. NMR with * H (CDCla) delta 1.74 (broad ß, 5 H). 2.73 (ß.20 H); exact mass (M + Li) *: calculated: 222.2270. Found: 222.2269 (CxoHXßNßl-i> • Fj Synthesis of hexafluorophosphate of ChierrodIDdichloro (l.4,7,10,13-pentaazacic1opentadecane) 3 108 mg (0.50 mmol) of the ligand 1,4,7,10,13-tetraazacyclopentadecane was dissolved in an inert atmosphere in a dry box. , in 15 ml of anhydrous methanol. 2 ml of a pyridine solution containing 0.50 mmol (80 mg) of anhydrous FeCl 2 was added to that solution with vigorous stirring. The resulting dark solution was heated at reflux for two hours with stirring, and then allowed to cool to room temperature, and then filtered. 20 ml of a clear methanolic solution of 163 mg of NH ^ PFβ was added to the filtrate. A yellow precipitate formed instantaneously, which was collected by filtration, washed with diethyl ether and dried under vacuum overnight. The yield, after drying, was 170 mg (0.338 mmol), which corresponds to a yield of 68% of theory. Analysis calculated for CxoHaoNßClatFeFβP-CHaOH: C, 25.07; H »5.41; N, 13.92. Found: C. 25.18; H, 5.60; N. 13.89. Mass spectrum (FAB, NBA matrix): m / z 306 (CFe (L) Cl + e:] - and mz 341 (ZFe (L) Cl xl *.

EXAMPLE Z Aj Synthesis of N- (p-toluenesulfonyl) - (R.R) -l, 2-diaminocyclohexane. To a stirred solution of 300 g, 2.63 moles, of (R, R) -l, 2-diaminocyclohexane in 5.00 liters of methylene chloride. at -10 ° C, a solution of 209 g, 1.10 moles, of p-toluensul onyl chloride in 5.00 l of methylene chloride was added dropwise over a period of 7 hours, maintaining the temperature at -5 to -10 ° C. The mixture was allowed to warm to room temperature while stirring overnight. The mixture was concentrated in vacuo to a volume of 3 liters and the white solid was filtered off. Then the solution was washed with 10? 1 liter of water and dried over magnesium sulfate. Removal of the solvent in vacuo gave 286 g (97.5% yield) of the product, as a yellow crystalline solid. NMR with * "- H (CDC13) delta 0.98-1.27 (m, 4 H), 1.54-1.66 (m, 2 H), 1.81-1.93 (m, 2 H), 2.34 (dt, J 4.0, 10.7 Hz, 1 H), 2.42 (s 3 H), 2.62 (dt J - 4.2, 9.9 Hz, ÍH), 7.29 (d, J = 8.1 Hz, 2 H), 7.77 (d, J = 8.3 Hz, 2 H) , MS (LRFAB - DTT-DTE) m / z 260 CM + H3-.

SJ Synthesis of N- (p-toluenesulfon I) -Nt- (Boc- (R, R) -1.2-diaocyclohexane To a stirred solution of 256 g, 0.955 moles, of N- (p-toluenesulfonyl) - (RR) -1.2-diaminocyclohexane, prepared as in example 2A in 1.15 liters of THF, was added 1.15 liters, 1.15 moles, of an aqueous IN NaOH solution, then 229 g, 1.05 moles of diterbutyl dicarbonate were added and The resulting mixture was stirred overnight, the layers were separated and the aqueous layer was adjusted to pH 2 with 1N HCl, and saturated with Na.It was then brought to the aqueous solution with 2 500 ml of sodium chloride. Methylene and ether combined the tract and the THF layer, and dried it over magnesium sulfate.The solvent was removed in vacuo to give a yellow solid.The crude product was purified by crystallization in a THF-ether mixture. -Keys, to give 310 g, 88.1% yield of the product as a white crystalline solid, mp 137-139 ° C. NMR with - "- H (CDCl, r) delta 1.05-1.28 (m, 4 H ), 1.44 (S, 9 H), 1161-1.69 (m 2 H). 1.94 - 2.01 (m 2 H), 2.43 (ß »3 H). 2.86 (broad ß l H) > 3.30 (wide d »J = 9.6 Hz» 1 H), 4.37 (wide d »J = 6.7 Hz» 1 H), 5.48 (broad d, J »4.6 Hz. 1 H)» 7.27 (d »J = 9.7 HZ »2 H >» 7.73 (d.J = 8.1 Hz. 2 H), MS (LRFAB NBA - Li) m / Z 375 CM + HD *.

C. Synthesis of Boc- (R, R-Cyc (Tß-gly-OMe To a stirred solution of 310 g, 0.841 mol, of N- (p-toluenesulfonyl) -N '- (Boc- (R, R) - The 2-diaminocyclohexane, prepared as in Example 2B, in 3.11 liters of anhydrous DMF, at 0 ° C, added 37.4 g »0.934 mol» of 60% NaH in oil »in portions, and then stirred the The resulting mixture was stirred for 30 minutes, then 142 g »0.925 mol» of methyl bromoacetate was added dropwise over 45 minutes and the mixture was allowed to warm to room temperature while stirring overnight. The solvent was then emptied and the residue was dissolved in 3 liters of ethyl acetate and 1 liter of water, the ethyl acetate solution was washed with 1 liter of saturated sodium bicarbonate, with 500 ml of saturated NaCl and dried over sodium sulfate. The solvent was removed in vacuo and the resulting oil was dissolved in. The crystallization by addition of hexanes gave 364 g (98% yield) of The product (TLC (92: 2 chloroform: methanol and silica gel / detn. UV) showed that the product contained about 5% of the starting material), as colorless needles; p.f. of the pure sample 151-152 ° C. NMR with AH (CDCl ,,.) delta 1.11-1.22 (m, 4 H); 1.45 (8 »9 H); 1.64-1.70 (m »3 H); 2.16 - 2.19 (m »1 H), 2.43 (8, 3 H), 3.34 - 3.40 (m, 2 H) »3.68 (8» 3 H), 4.06 (ABq, J = 8.3 Hz, 2 H); 7.82 (d, J = 8.3 HZ »2 H); MS (LRFAB - DTT - DTE) m / Z 441 CM + H3 - * -.

D. Synthesis of Boc- (R, R) -Cyc (Tß) -Gly-QH To a stirred solution of 217 g, 0.492 mol »of Boc- (R» R) -Cyc (Ts) -Gly-OMe impure, prepared as in example 2C, in 1.05 liter of methanol, ß slowly added a 2.5N solution of 296 ml, 0.737 mol of aqueous NaOH and the resulting solution was stirred for two hours. The solvent was mined in vacuo and the residue was dissolved in 1.5 liters of water. The solution was filtered to remove a small amount of solid and then washed with 7 x 1 liter of ether to remove the impurity (compound IB) which, by drying the combined washes, over magnesium sulfate and removing the solvent in vacuo, resulted in the recovery of 8.35 g. Then, the pH of the aqueous solution was adjusted to 2 with 1 N HCl and the product was extracted with 3? 1 liter of ethyl acetate. The tracts were combined, washed with 500 ml of saturated NaCl and dried over magnesium sulfate. The solvent was removed in vacuo and the residual ethyl acetate was removed by co-evaporation with 500 ml of ether and then with 500 ml of methylene chloride to give 205 g (97.6% yield) of the product as a white foam. NMR with * «-H (CDC13) delta 1.15-1.22 (m, 4 H), 1.48 (8» 9 H). 1.55 - 1.68 (m »3 H); 2.12 - 2.15 (m. 1 H) »2.43 (8. 3 H). 3.41 - 3.49 (m »2 H), 3.97 (ABq J = 17.9 Hz, ¿U = 69.6 HZ, 2 H). 4.79 (8 broad, 1 H); 7.31 (d, J = 8.1 HZ, 2 H), 7.77 (d, J = 8.3 HZ, 2 H), 8.81 (8 broad, 1 H); MS (LRFAB, NBA -Li) m / z 433 CM + H] *.

E. Synthesis of N- (p-toluenesulfonyl) - (SS) -1.2-diaminocyclohexane To a stirred solution of 300 g »2.63 moles, of (S» S) -1.2-diam nocyclohexane in 5.00 liter of methylene chloride at -10 ° C., a solution of 209 g, 1.10 mole, of p-toluene sulfonyl chloride in 5.00 liter of methylene chloride was added, dropwise, over a period of 8 hours, maintaining the temperature at -5 to -10 °. C. The mixture was allowed to warm to room temperature while stirring overnight. The mixture was concentrated in vacuo to a volume of 3 liters and the white solid was removed by viltration. Then the solution was washed with 10? 1 liter of water and dried over magnesium sulfate. Removal of the solvent in vacuo gave 389 g (98.3% yield) of the product as a yellow crystalline solid. NMR with J-H (CDCl ,,.) delta 0.98 - 1.27 (m. 4 H), 1.55-1.66 (m. 2 H), 1.81 - 1.94 (m, 2 H), 2.32 (dt J = 4.0, 10.9 Hz, Í H), 2.42 (s, 3 H), 2.61 (dt J = 4.0, 9.9 Hz, Í H), 7.30 (d, J = 7.9 HZ, 2 H), 7.77 (d, J = 8.3 Hz, 2 H) MS (LRFAB, GT - HCl) m / Z 269 CM + IH: -.

F. Synthesis of N- (P-toluene sulfonyl 1) -Nf- (Boc- (SS) -1.2-diareino-cyclohexane To a stirred solution of 289 g, 1.08 moles, of N- (p-toluene sulfonyl) - ( S, S) -l, 2-diaminocyclohexane, prepared as in example 2E, and 1.29 liter of THF, 1.29 liters, 1.29 moles.- of a 1 N aqueous solution of NaOH was added, then ß added 258 g, 1.18 moleß, diterbutyl dicarbonate and the resulting mixture was stirred overnight.The solid was filtered off and washed with THF.The THF layer was separated and the aqueous layer was adjusted to pH 2 with IN HCl and. Saturated with NaCl, then the aqueous solution was extracted with 2 500 ml of methylene chloride and combined with the tract and the THF layer, washed with 500 ml of NaCl and dried over magnesium sulfate. The solvent was evaporated to give a yellow suspension, crystallization with the addition of ether gave 364 g (91.9% yield) of the product, as colorless needles, mp 137-139 ° C.

NMR with -HH (CDC13) delta 1.06 - 1.31 (m, 4 H), 1.44 (S 9 H), 1.60 - 1.69 (m 2 H), 1.95 - 1.99 (m, 2 H), 2.42 (s, 3 H), 2.86 (broad s, l H), 3.30 (d wide a, J = 2.6 Hz, 1 H), 4.41 (wide d, J = 7.3 Hz, 1 H), 5.54 (broad d, J = 5.4 Hz , 1 H), 7.28 (d, J = 8.1 HZ, 2 H), 7.73 Od. J s 8.3 Hz. Z H); MS (LRFAB, NBA - HCl) m / z 369 CMH-H] * 4-.

G. Synthesis of Boc- (S, S) -Cyc (Tß) -gly-OMe To a stirred solution of 364 g, 0.989 mol, of N- (p-toluenesulfonyl) -N '- (Boc- (S, S ) -l, 2-diaminocyclohexane, prepared as in Example 2F »in 3.66 liters of anhydrous DMF» at 0 ° C »was added 47.4 g» 1.19 moles »of 60% NaH in oil» in portions »and the resulting mixture was stirred for 1.5 hours, the mixture was warmed to room temperature and stirred for another 30 minutes and then cooled again to 0 ° C. 180 g »1.24 moles» of methyl bromoacetate were added dropwise during 30 minutes »and the mixture was allowed to warm to room temperature while stirring overnight After stirring for 17 hours the ßol vent was removed in vacuo and the residue was dissolved in a mixture of 3 liters of ethyl acetate and 1 liter of water The layers were separated and the ethyl acetate solution was washed with 1 liter of sodium bicarbonate, 1 liter of water, 2 500 ml of saturated NaCl and then dried over sulphate. of magnesium The solvent was removed in vacuo and the resulting oil was dissolved in ether. Crystallization by the addition of heanos gave 290 g of the crude product, as yellow needles. Other IBO gs were recovered from the filtrate, as an oil. TLC (98: 2 chloroform / silica gel / UV dtn) showed that both the solid and the oil contained starting material. NMR with AH (CDCl.,) Delta 1.06 - 1.29 (m, 4 H), 1.44 (8, 9 H); 1.58 - 1.66 (m »3 H). 2.17-2.19 (m.h. H); 2.43 (s »3 H); 3.28 - 3.43 (m.2 H); 3.68 (S, 3 H), 4.25 (ABq, J = 18.5 Hz, u = 115 Hz, 2H), 4.76 (8 broad, 1 H), 7.31 (d, J = 8.3 HZ, 2 H), 7.83 ( d, J = 8.3 Hz. 2 H); MS (LRFAB, NBA - Li) m / Z 447 MS + HD *.

H. Synthesis of Boc- (S, S) -Cyc (Tß) -Gly-QH To a stirred solution of 197 g, 0.447 mol, of Boc- (S, S) -Cyc (Ts) -Gly-Ome impure, prepared as in example 2G, in 925 ml of MeOH, a 2.5 N solution of 268 ml, 0.670 mol of aqueous NaOH was slowly added, and the solution was stirred for two hours. The solvent was removed under vacuum and the residue was dissolved in 1 liter of water. Was the solution washed with 4? 1 liter of ether, to eliminate the impurity (compound 2F) which, upon drying the combined washes over magnesium sulfate and eliminating the solvent in vacuo, resulted in the recovery of 14.8 g. Then the pH of the aqueous solution was adjusted to 2 with 1N HCl, and the product was brought with 3? 2 liter of ethyl acetate. The combined extracts were combined, washed with saturated NaCl and dried over magnesium sulfate. The solvent was removed in vacuo to give 171 g (89.7%) of the product as an oil which crystallized on standing. NMR with AH (CDC13) delta 1.10 - 1.22 (m, 4 H), 1.45 (8 9 H), 1.55 - 1.6B (m, 3 H), 2.13 - 2.16 (m, 1 H); 2.43 (8, 3 H>, 3.39 - 3.41 (m, 2 H), 4.00 (ABq, J = 18.1 Hz, / \ u = 80.4 HZ, 2 H), 4.82 (8 broad, 1 H), 7.31 > (d, J «8.3 Hz, 2 H), 7.75 (d, J« 8.3 HZ, 2 H), 9.28 (broad S, 1 H); MS (LRFAB, NBA - Li) m / Z 433 CM + H3 *.

I. Synthesis of Boc- (S, S) -Cyc (Ts) -Gly-Gly-OEt To a stirred solution of Boc- (S, S) -Cyc (Ts) -Gly-OH, prepared as in Example 2H (26.7 g, 62.5 mmol) in 690 ml of anhydrous, degassed DMF was added 10.1 g, 75.0 mmol, of HOBT and 14.4 g, 75.0 mmol, of EDC-HC1. After the resulting solution was stirred for 30 minutes, 9.60 g was added. 68.8 mmoles, of glycine ethyl ester hydrochloride, and η adjusted the pH to 8 with TEA. After stirring for 2.75 days, the solvent was removed in vacuo. The residue was dissolved in a mixture of 1 liter of ethyl acetate and 1 liter of water and the layers were separated. The brine layer was brought with 1 liter of ethyl acetate and combined with the tractoß. The ethyl acetate solution was washed with 1 liter of 0.1 N HCl, with 1 liter of saturated sodium bicarbonate, with 500 ml of saturated sodium chloride and dried over magnesium sulfate. The solvent was removed under vacuum to give 30.2 g (94.4% yield) of the product, as a white foam. NMR with * H (CDC13) delta 1.19 - 1.23 (m, 3H), 1.28 (t, J = 7.05 HZ, 3 H), 1.42 (8, 11 H), 1.63 - 1.71 (m, 2 H), 2.16 - 2.18 (m, 1 H), 2.43 < S, 3 H), 3.50 - 3.57 (m, 2 h), 3.83 (ABq, J = • 17.7 Hz, delta V = 35.7 Hz, 2 H), 4.01 (dABq, J «6.05, 17.92 HZ, delta V = 28.9 Hz, 2 H), 4.20 (C, J = 7.3 Hz, 2 H), 4.88 (8 broad, 1 H). 7.31 (d, J "8.3 Hz, 2 H), 7.36 (8 broad, 1 H), 7.73 (d, J = 8.3 Hz, 2 H); MS (LRFAB, NBA-HCl) m / Z 512 CM-HD *.

J. Synthesis of the TFA salt of (S, S) -Cyc (Ts) -Gly-Gly-QEt To a stirred solution of 30.1 g, 58.8 mmol, of Boc- (S, S) -Cyc (Ts) -Gly-Gly-OEt, prepared as in Example 21, in 265 ml of methylene chloride, 63 ml of TFA was added and the resulting solution was stirred for 30 minutes . The solvent was removed in vacuo and the residual TFA was coevaporated with 2 x 1 liter of methylene chloride and 1 liter of ether. The oil was triturated with 2 x 1 liter of ether and the ether was decanted. The resulting foam was evacuated to give 3.7 g (assuming a quantitative yield) of the product, such as a cinnamon powder. NMR with * H (CDC13) delta 0.96-1.23 (m, 4 H); 1.25 (t, J = 7.3 Hz, 3 H), 1.51 - 1.66 (m, 3 H), 2.12 - 2.26 (m, 1 H); 2.41 (S, 3 H), 2.98 - 3.10 (8 broad, 1 H), 3.67 - 3.71 (m, 1 H), 4.04 (ABq, J = 17.7 Hz, delta v = 154 Hz, * 2 H), 4.04 (d, J = 4.4 HZ, 2 H), 4.17 (C, J = 7.3 Hz, 2 H), 7.29 (d, J = 8.3 Hz, 2 H), 7.70 (d J = 8.3 Hz, 2 H); 8.04 (s broad, 1 H), 8.14 (s broad, 3 H> MS (LRFAB, NBA - HCl) m / Z 412 CM + H3 *.

K. Synthesis of Boc- (R »R) -Cyc (Ts) -Gly- (S» S) -Cyc (Ts) -Gly-Gly-OEt. To a stirred solution of 25.1 g, 58.8 mmoles, of Boc- (R, R) -Cyc (Ts) -Gly-OH, prepared as in example 2D, in 650 rolls of DMF anhydrous and degassed, 9.54 g was added, 70.6 mmoles, of HOBT and 13.5 g, 70.6 mmoles, of EDC-HC1. After the resulting solution was stirred for 30 minutes, 33.6 g, 58.8 mmol, of the TFA salt of (S, S) -Cyc (Ts) -Gly-Gly-OEt was added. prepared as in example 1J, and the pH was adjusted to 8, with TEA. After stirring for 2.75 days, the solvent was removed in vacuo. The residue was dissolved in a mixture of 1 liter of ethyl acetate and 1 liter of water and the layers were separated. The ethyl acetate solution was washed with 2 x 1 liter of 0.1 N HCl, with 2 x 1 liter of saturated sodium bicarbonate, with 500 ml of saturated sodium chloride and εeec on magnesium sulfate. The solvent was removed under vacuum to give 47.5 g (98.4% yield) of the product, such as a cinnamon foam. NMR with AH (CDCl ,,.) delta 1.12 - 183 (, 26 H). 2.21 -224 (m, 2 H), 2.42 (S, 3 H), 2.43 (8, 3 H), 3.36 - 3.51 (8, broad, 2 H), 3.68 - 3.96 (m, 6 H), 4.00 ( d, J * 5.4 Hz »2 H); 4.19 (C l = 7.1 HZ »2 H), 4.72 (8 broad, 1 H), 6.78 (8 broad, 1 H), 7.31 (d, J = 8.1 Hz, 4), 7.46 (broad s, 1 H) 7.79 (m, 4 H); MS (LRFAB »NBA-HCl) m / Z 820 CM + H 3 *.

L. Synthesis of Boc- (R, R) -Cvc (Ts) -Gly- (S.S) -Cyc (Ts) -Gl -Gly-OH To a stirred solution of 47.4 g »57.8 mmoles» of Boc- (R, R) -Cyc (Ts) -61y- (S, S) -Cyc (Ts) -Gly-Gly-OEt, prepared as in example 2K . in 240 ml of MeOH, a 2.5 N solution of 34.7 ml, 86.7 mmoles of aqueous NaOH was added, and the resulting solution was stirred for two hours. The solvent was removed under vacuum and the residue was dissolved in 1 liter of water. The aqueous solution was washed with 2 x 1 liter of ether and the pH was adjusted to 2 with 1 N HCl. The solution was then saturated with NaCl and extracted with 3 x 1 liter of ethyl acetate. The combined extracts were removed and the solvent was removed in vacuo. The residual ethyl acetate was separated by coevaporation with methylene chloride and the resulting foam was vacuum dried to give 45.7 g (99.7% yield) of the product, as a cinnamon powder. NMR with - "- H (CDCl-delta 1.16 - 1.75 (m, 23 H), 2.13 - 2.17 (ra, 2 H), 2.41 (s, 3 H), 2.42 (8, 3 H), 3.49 - 4.16 ( m, 10 H), 4.53 (broad s, 1 H), 7.01 (broad s, 1 H), 7.30 (d J = 8.1 Hz, 4 H); 7.40 (ß, broad, 1 H). 7.79 (d.J = 8.1 Hz. 2 H); 7.86 (d, J * = 7.7 HZ.2H) »10.40 (8 broad, 1 H); MS (LRFAB, NBA-HCl) m / Z 792 CM + H3 *.

M. Synthesis of the TFA salt of (R.R) -Cyc (Ts) -G1v- (S, S) -Cyc (Ts) -Gly-G1y. To a stirred solution of 45.5 g »57.5 mmoles) of Boc- (R» R) -Cyc (Ts) -Gly- (SS) -Cyc (Ts) -Gly-Gly-OH »prepared as in example 2L» in 260 ml of methylene chloride »60 ml of TFA was added. The resulting solution was stirred for 30 minutes and the solvent was removed in vacuo. The residual TFA was separated by covaporating with 3 x 1 liter of methylene chloride and triturating the resulting foam with 1 liter and 2 x 750 ml of ether, decanting the ether each time. After drying under vacuum, 47.4 g (100% yield) of the product was obtained as a white matte powder. NMR with iH (CDCl ,,.) delta 1.05 - 1.31 (m, 9 H), 1.48 -1.63 (m, 5H), 2.11 - 2.21 (m, 2 H), 2.40 (S, 3 H), 2.42 (8 , 3 H), 3.25 (8 broad 1 H), 3.60 - 3.80 (m, 3 H) »3.83 - 4.19 (m > 6 H). 6.94 (broad S, 1 H), 7.31 (m, 4 H), 7.69 (m, 4 H); 7.83 (s broad, 3 H); 13.17 (broad s, 2 H). MS (LRFAB, DTT-DTE) m / Z 692 CM + -H3 *.

N. Synthesis of cyclo-C (R »R) -cyc (Tß) -Gly- (S, S) -Cyc (Ts) -Gly-Glv-] To a stirred solution of 32.2 g, 40.0 mmoles, of the salt of tFA of (R, R) -Cyc (Tß) -Gly- (S, S) -Cyc (Tß) -Gly-Gly-OH, prepared as in Example 2M »in 10.0 liters of DMF anhydrous» degassed »to -78 ° C was added 13.4 g »48.8 mmoles» of DPPA. The pH of the solution was then adjusted to 8 with TEA and the solution was allowed to stand for six hours at -78 ° C. The pH was readjusted to 8 with TEA and the solution was heated at -45 ° C for 24 hours. After readjusting the pH as before, the solution was allowed to warm to -40 ° C for 24 hours. The pH was adjusted as before and the solution was allowed to stand at -20 ° C for 24 hours. Again the pH was adjusted as before and the solution was allowed to warm to 2 ° C for 24 hours. The pH had dropped only slightly. The pH was readjusted as before and the solution was allowed to stand at 2 ° C for another 24 hours, and after that time the pH had not changed. The solution was divided equally between six 4-liter beakers and añadió añadió each added 1.1 liter of water. Then η added a total of 5.00 kg of ion exchange resin, in mixed bed, to the solution (equally divided between the six beakers) and the mixtures were stirred for six hours. The reflux was filtered and washed with DMF. The solvent was then removed under vacuum and the solid residue was dissolved in 100 ml of MeOH and filtered to remove the finely divided solids. The solution was then concentrated in vacuo at a volume of 25 ml and ether was added periodically as the crystal continued to give 22.2 g (82.5% yield) of the product as colorless needles, m.p. 190-200 °. NMR with AH (CDCl ,,) delta 0.87 - 2.13 (m, 16 H), 2.41 (8. 3 H), 2.45 (8, 3 H), 3.56 - 3.97 (m, 10 H), 6.66 (8 broad, 1 H), 7.18 (8 broad, 1 H); 7.34 (d, J = 8.1 HZ, 4 H), 7.65 (8 broad, H), 7.71 (d, J = 7.3 Hz, 2 H), 7.89 (d, J = 7.3 Hz, 2 H); MS (LRFAB, NBA - Li) m / z 680 CM + HD-. 0. Synthesis of 2,3- (R, R) -8,9- (S, S) -bis-cyclohexane-1, 4,7,10, 13-pentaazacic1 opentadecane To a stirred solution of 19.4 g, 28.8 mmoles, of Cyclo-C (R, R) -Cyc (Ts) -βly- (S, S) -Cyc (Ts-Gly-Gly), prepared as in example 2N, in 475 ml of anhydrous THF, a solution of 345 ml, 345 mmol, 1.0 M LiAlH in THF, dropwise, for 30 minutes.The yellow homogeneous solution was left to reflux for 20 hours (during which time it had become heterogeneous) and then cooled to 0 ° C. The mixture was then quenched by the dropwise addition of 50 ml of a 10% solution of sodium sulfate, while cooling in an ice bath, the solids were removed by filtration under an Ar blanket and the THF, to give an oil that crystallized rapidly, the solids were refluxed with 1 liter of anhydrous THF for one hour and the mixture was filtered and the solvent was removed in vacuo as before, then the solids were allowed to reflux. a mixture of 1 liter of THF and 500 ml of MeOH for one hour, and worked as before. e? traccioneß in anhydrous THF, the solids were combined and filtered off. The solvent was removed under vacuum and the yellow foam was dried by azeotroping water with 1.75 l of toluene under vacuum at 90 ° C. The solids were then refluxed with 1 liter of blood for 30 minutes, and the heated solution was transferred to a tared flask and the solvent was removed in vacuo to give 6.1 g of an oil which crystallized on standing. The remaining solids were left to reflux with hairs, as before, and 1.4 g of an oil that crystallized upon standing was obtained. The solids were then dissolved in MeOH and one liter of toluene was added. The solvent was removed in vacuo and any remaining water was removed to form azeotrope with one liter of toluene, and then with 3 x 1 liter of hexanes. The resulting fine powder was refluxed with 1 liter of hexanes for two hours under argon and filtered into a tared flask. The solvent was removed under vacuum to give 1.7 g of oil which crystallized on standing. The crystalline residues of the 3 extracts were dissolved in hexanes and combined. A small amount of turbidity was removed by filtration and the solution was concentrated to yield 5.3 g (57% yield) of product, as a pale yellow, crystalline solid. Recrystallization from acetonitrile gave 4.47 g (48.0% yield) of a colorless crystalline solid, e.g. F. 107-108 ° C. NMR with - "- H (CDCl, r) delta 0.95 - 1.01 (m, 4 H); 1.19 - 1.24 (m, 4 H), 1.70 - 1.73 (m, 4 H), 1.97 (broad s, 5 H), 2.08 - 2.14 (m 8 H). 2.49 - 2.68 (m 6 H), 2.74 - 2.80 (m, 2 H), 2.85 - 2.90 (m 2 H); 2.94-2.99 (m, 2 H); MS 8LRFAB, NBA) m / z 324 CM + H] *. Analysis calculated for xßH3-, Nß: C »66.83; H » 11. 53; N »21.65. Found: C »66.80; H »11.44; N »21.71.

P. Synthesis of Chierro (III) chloride-dichloro (2 »3- (R» R) -B »9- (S, S) -bis-cyclohe- ano-l, 4,7,10» 13-pentaazacyclopentadecane3 It was dissolved, under an inert atmosphere, in a dry box, 199 mg (0.615 mmol) of ligand 2,3- (R, R) -8,9- (SS) -bis-cyclohexane-1.4.7.103-tetraazacyclopentadecane in 10 ml of anhydrous methanol solution contained 0.615 mmol (100 mg) of anhydrous FeCl3. The resulting dark yellow-orange solution was heated to reflux for half an hour, with stirring, and then allowed to cool to room temperature and filtered. The filtrate was reduced to dryness and redissolved in 25 ml of hot absolute ethanol and filtered through Cel te. The ethanolic solution was reduced to a volume of about 10 ml. Diethyl ether was added to this ethanolic solution to the point of turbidity. The solution was allowed to settle without moving it for 16 hours, after which a yellow microcrystalline precipitate had formed. The yellow solid was isolated by filtration, washed with diethyl ether and dried under vacuum overnight. The yield after drying was 235 mg (0.486 mmol) »which corresponds to 79% of the theoretical yield. Analysis calculated for Ca.oH3OFeCl3-CH3CH30H: C »45.25; H., 8.16; N. 13.19; Cl, 20.03. Found: C »44.97; H, 8.07; (\ J.13.01; Cl, 19.88) Mass spectrum (FAB, NBA matrix): m / z was observed 449 (CFe (L) Cin + e3-- and m / z 431 (CFeíDCl ^ D *.

EXAMPLE 3 A. Syntheses of N.N * '- bis (chloroacetyl) lR.2R-diaminocyclohexane. 6.98 g was dissolved. 61.13 mmole »of LR» 2R - (-) - diaminocyclohexane in 75 ml of alcohol-free CHC13 »in a 2-ml, 4-neck, round bottom flask. together with 37 ml of water »under argon. Two Normag drip funnels were connected to the reaction flask and charged separately with 15 ml »188.3 mmol» of chloroacetyl chloride in 88 ml of CHCl3. alcohol-free »and with 24.1 g» 174.4 mmol »of potassium carbonate in 918 ml of water. An internal thermometer was inserted into the reaction flask. After cooling the two-phase mixture in the reaction flask "to 0 ° C in an ice bath" the addition was started from the two dropping funnels "in such a way" that the ratio of each solution was approximately equal. »During a period of 1 hour 20 minutes. During the addition, an ice and salt bath was used to moderate the temperature, keeping it between 3 and -3 ° C. An ice core formed inside the reaction flask, which did not appear to impede agitation. The reaction flask was removed from the ice bath at the end of the addition and stirred for 2 hours 20 minutes. The lower layer of chloroform appeared to have a considerable amount of clear solid "at the temperature of the ice bath" but dissolved as the reaction heated. The reaction mixture was placed in a separatory funnel, some more chloroform was added, and the layers were separated. The aqueous layer was extracted with another portion of chloroform and the combined chloroformic layers were washed with water and then saturated NaCl, dried over sodium sulfate and separated to a brownish white solid. This solid was stirred overnight with about 450 ml of ether, then filtered, leaving part of the color in the ether, which gave a crude solid, 13.68 g, 41.60 mmoles, 84.4% yield. NMR with (CDC13400 MHz) delta 1.34 (m, 4H), 1.80 (m, 2H), 2.08 (m 2H), 3.74 (m 2H), 3.99 (ABq, J = 15.1 Hz, dn «8.2 HZ, 4H), 7.26 (broad S, 2 H). NMR with - "- H (CDCl, r 100 MHz) delta 24.59, 32.07, 42.45, 53.94, 166.65 MS (FAB, NBA-LiCl matrix): m / z (relative intensity) 273 (100) CM + Li: J-, 275 (71) CM + LÍ3-.

B. Synthesis of N-tosyl lgl icyl-lR, 2R-diaminocyclohexane 10.0 g, 87.57 mmol) of 1R.2R-diaminocyclohexane was dissolved in 150 ml of dry DMF, under argon, and cooled to -10 °. C. Separately, 10.04 g, 43.62 mmoles of N-tos lgl icina, 6.75 g »44.08 mmoles, of 1-hydro? benzotriazole and 8.45 g, 44.05 mmol "of 1-ethi 1-3- (3-d-methylaminopropyl) carbodimide hydrochloride in 150 ml of dry DMF" and was cooled to -10 ° under argon. The latter solution was added to the diaminocyclohexane solution at -10 ° C. by means of a cannula. After 2 hours at eßa tempeartura. η added 8 ml of water and left the reaction to warm at 0 ° C for one hour, then at room temperature for the next half hour. The solvent was removed on the rotary evaporator, under reduced pressure. The residue was heated at 40-42 ° C with 150 ml of water, added in small portions, with stirring. After 25 minutes this solution was filtered. The large white precipitate was the bis-adduct (5.55 g). Exactly 68 ml of the filtrate was recovered by repeated e9 traction co9? 50 ml of dichloromethane. The combined organic phase was dried (sodium sulfate), filtered and the solvent was removed. The resulting white solid, containing some residual DMF, was redissolved in 30 ml of dichloromethane, and added dropwise to a stirred solution of ether 9: 1: heineum (250-300 ml), which It gave an immediate precipitate that was stirred overnight and then filtered. That procedure was repeated by stirring for three hours instead of overnight. After drying the white product in the vacuum line, 2.36 g, 7.25 mmol, was obtained, equivalent to a yield of 36.7% for the entire reaction. NMR with • * -H (CDCl ,, 400 MHz) delta 1.10 - 1.34 (m, 4H), 1.70 (d, J = 9.7 HZ, 2 H), 1.81 - 1.97 (2 m 2H), 2.41 (8 .3H), 2.51 (td, J = 10.2 »3.8 Hz, ÍH), 3.53 (m + ABq, J = 16.9 Hz, dn = 51.6 HZ, 3H), 3.69 (8 broad, 3 H), 6.84 (d, J * • 9.1 Hz, ÍH), 7.30 (d.J = 8.3 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H); NMR with * - * C (CDC13 100 MHz) delta 21.48, 24.87, 24.97, 32.08, 35.16, 46.09, 54.85, 55.78, 127.15, 129.85, 136.02, 143.84, 168.69. MS (GTHC1): m / z 326 (100) CM + H3"^.

C. Synthesis of 2R, 3R, 8R, 9R-bis (cyclohexane) -13-p-toluene-sulfone 1-11.4.7, 10, 13-pentaazacic-opentadecan-6, 11, 15-trione 1.11 g, 3.42 mmol was combined of Np-toluenesulfonyl-glycite-IR »2R-diarynocrylamide and 0.913 g, 3.42 mmol, of N, NT-bis-chloroacetyl) -lR, 2R-diaminocyclohexane, in a one-liter flask and added 650 ml of dry N, N-dimethylacetamide, the flask was made inert, and after 10 minutes sodium hydride was added directly to the homogeneous mixture and the reaction flask was placed in a year of 70 ° C. the internal temperature reached 45-50 ° C, the evolution of gas became constant, the temperature of the oil bath stabilized at around 65 ° C with some excursions of around 60 to 75 ° C. During the night the reaction mixture became After heating for 17 hours, the reaction flask was removed from the bath and allowed to cool, the polar solvent was removed under reduced pressure and the yellowish ceite in a vacuum line. The residue was treated with 300 ml of diechloroethane and washed with 40 ml of water and twice with inert sodium chloride (40 ml each time). After combining, the aqueous layers were washed again with 100 ml of d-chloromethane. The combined organic layers were dried over sodium sulfate, filtered and separated to 2.14 g of a viscous yellow oil, which was placed in the vacuum line. This residue is chromatographed using 5% ammonium hydroxide / 9% ethanol / 90.5% methylene chloride. By TLC on silica, using the same system, Rf - 0.25. The fractions containing the correct point were combined and evaporated to a slightly matt white solid, 0.890 g, 1.71 mmol, 50.1% yield. NMR with - * - H (CDC13 300 MHz) delta 0.92 - 2.1 (several m, 15H), 2.27 (m, ÍH), 2.41 (8, 3H), 3.10 (ABq, J = 16 Hz, dn = 34.2 HZ, 2H), 3.39 (m, ÍH); 3.58 (m, 3H), 3.83 (m, HH), 4.08 (d, J = 17.6 HZ, HH), 4.39 (d, J = 17.4 Hz, 1H9, 7.30 (m, 3H), 7.44 (d.J = 5.9 Hz, HH), 7.76 (d, J = 7.8 Hz, 2H), 8.05 (d, J = 8.4 Hz, HH), NMR with * »C (CDC13, 100 MHz) d 21.39» 24.20 »24.69, 24. 87 (double intensity), 31.49, 31.54, 31.58, 32.43, 47.01, 52.19, 52.25, 52.49, 52.97, 55.63 »58.36, 127.65, 1290.67, 135.28, 143.97, 167.52, 170.04, 172.84, MS (NAB matrix FAB) -Li): m / z (relative intensity) 526 (100) CM + LÍ3-; 370 (29) EM + Li-Ts * J-.

P_¡ Synthesis of 2R, 3R, BR, 9R-bis (cyclohexane) -l, 4,7,10,13-pentaazac c1 opentadecane 4.072 g, 7.84 mmoles, of 2R.3R.8R.9R-bis were placed (cyc 1 oheum) -13-p-to1uensu1foni 1-1, 4, 7, 10, 13-pentaazaci c1o-pentadecan-6, 11, 15-trione in a one liter flask, under an argon atmosphere, and 220 ml of dry 1,2-dimethoxyethane (DME) was added. The powder melted and did not dissolve appreciably. It was partially crumbled with a spatula and stirred in a cold water bath while 140 ml, 70 mmol, of lithium aluminum hydride (0.5 M in DME) was added in portions over a period of 10 minutes. The solution became turbid initially. and undissolved lumps of the compound were present. After that, he had added about 70 ml. the solution was quite homogeneous, with only a few remaining undissolved pieces, which appeared to dissolve with gaß detachment. The heating was started after a few minutes and the solution became rapidly heterogeneous and yellow in color. The reaction mixture was allowed to reflux overnight. The reflux ended after 16.5 hours. The reaction mixture was cooled in a cold water bath, then in a -1B ° C bath. 2.2 ml of water was added cautiously in small amounts, for a period of 5 to 10 minutes, followed more rapidly by 2.2 ml of 15% NaOH. then by 6.6 ml of water. Stirring was continued for two hours in the ice bath. 210 ml of tetrahydrofuran (THF) was added and continued stirring for one hour. The thick white suspension was allowed to settle and filtered with a filter transfer dye (Whatman No. 1 paper). The filtrate was separated. The white residue was stirred with THF (150 ml) and filtered in the first separate filtrate. The solvent was removed under reduced pressure and the residue was placed in the vacuum line. The resulting yellow-white solid was extracted with hot dry hexane (initially 70 ml, 65 ° C.; then 15 additional ral) and filtered through a filter transfer device (Whatman No. 50 paper) and the solvent was removed under reduced pressure. This crude product, weighing about 1.5 g, was dissolved in about 60 ml of hot acetonitrile (at more than 70 ° C), then filtered (filter transfer device, Whatman 1 * 50 paper), concentrated in more than half, it was reheated to dissolve all the white solid, then left to cool slowly to room temperature. White crystals were obtained, 0.923 g, 2.85 mmol, 36.4% yield. NMR with * H (CßDβ »300 MHz) d 0.75-1.21 (several m, 8H), 1.23-2.19 (several m, 17H), 2.36-2.61 (several H, 6H), 2. 61-2.73 (m, 2H), 2.74-2.85 (m, 2H). 2.90 (d.J = 7.5 Hz, 2H); NMR with A »C (CßDβ» 75 MHz) d 25.48. 25.56 > . 32.41, 32.48. 46.50. 47.B2, 49.56. 61.86. 62.88. Analysis calculated for C ßH -, Nß: C. 66.83; H, 11.54; N. 21.65. Found: C. 66.66; H. 11.46; N, 21.78.

E. Synthesis of Chloride (III) hexafluorophosphate dichloro (2,3- (R.R) -B.9- < RR) -biß-cyclohexane-1,4,7,10,13-pentaazac-c-o-pentadecane) ] In an inert atmosphere in a dry box, 97 mg (0.30 mmol) of the ligand 2R »3R» 8R »9R-bis (skyhear) -1,4,7,10,13-tetraazacyclopentadecane was dissolved in a dry box. 15 ml of anhydrous methanol. To that solution, with vigorous stirring, 2 ml of pyridine solution containing 48 mg, 0.30 mmol, of anhydrous FeCl3 was added. The resulting dark brown solution was heated at reflux for three hours, with stirring, and then allowed to cool to ambient temperature and then filtered. To the filtrate was added 20 ml of a clear methanolic solution of 120 mg of NH ^ PFß. The solution was evaporated to dryness and 2 ml of anhydrous acetonitrile was added to the resulting solid. This mixture was vigorously stirred for two hours and then the resultant yellow filtrate was filtered and evaporated to dryness. The resulting yellow solid was dissolved in hot ethanol and filtered. The solution was evaporated to dryness and the resulting yellow solid was collected by mediantae filtration in a diethyl ether wash. The yellow precipitate was dried under vacuum overnight. The yield, after drying, was 75 mg. which corresponded to a yield of 42% of the theoretical. Analysis calculated for CißH3 NßCl3FβFeP: C »36.35; H, 6.28; ! M. 11.78. Found: C, 36.37; H. 6.34; N. 11.58.

EXAMPLE 4 A. Synthesis of Boc-DAla-Ala-OEt To a solution of 25.0 g, 132.1 mmol, of Boc-DAIa in 1450 ml of DMF, was added 19.8 g, 129.3 mmol, of HOBT-H30 and 28.0 g, 146.3 mmol, of EDC-HC1, and the resulting solution was allowed to stir at room temperature for 30 minutes. To that solution was added 20.3 g, 132.1 mmol, of alanine ethyl ester hydrochloride and 20.4 ml, 146.3 mmol, of TEA and the reaction was allowed to stir for three days (for convenience). The DMF was evaporated and the residue was partitioned between 500 ml of water and 500 ml of ethyl acetate. The ethyl acetate solution was washed with 250 ml of NaHSO 4, with 250 ml of water and with 250 ml of saturated sodium bicarbonate with 250 ml of samue and dried over sodium sulfate. Filtration and concentration yielded 31.7 g (83% yield) of the desired dipeptide, as a white foam. NMR with * H (DMSO-d «,) delta 1.14 (d, J = 7.-4 Hz, 3 H), 1.16 (tt J» 7.4 Hz, 3 H), 1.24 (d, J «7.0 Hz, 3 H), 1.36 (ß, 9 H), 3.96-4.09 (m, 3 H); 4.17 - 4.22 (apparent quintet » J = 7.4 HZ, 1 H), 6.77 (d, J = 7.7 HZ, 1 H), 8.09 (d, J = 7.0 Hz. 1 H), MS (LRCI. CH.) M / z (relative intensity) = 317 (5) CM + C3Hß3 *** »289 (60) CM + H3 *.

B. Synthesis of Boc-Ala-Ala-OH To a suspension of 15.0 g. 93.6 mmol. of the dipeptide in 192 ml of THF. 192 ml of a 0.5 N NaOH solution was added. 26.6 g, 121.7 mmol, of diterbutyl dicarbonate was added at once to the resulting solution. The pH of the reaction was maintained at around 10 for 5 hours and the mixture was allowed to stir overnight. The pH of the reaction was again adjusted to about 10 and the solution was brought with 2? 100 ml of ethyl acetate. The pH of the aqueous layer was adjusted to about 3.5 with aqueous potassium bisulfate and this mixture was brought with 3? 100 ml of ethyl acetate. The combined tracts were dried in magnesium sulfate, filtered and concentrated to give 20.7 g (85% yield) of the desired product as a white powder. NMR with - «- H (DMS0-dβ) delta 1.16 d, J = 6.8 Hz, 3 H), 1.28 (d, J = 7.3 HZ, 3 H), 1.38 (S, 9 H), 3.95 - 4.09 (m , 1 H), 4.20 (quintet, J = 7.3 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 8.00 (d, 7.3 HZ, 1 H), MS (HRFAB, NBA - Li) m / Z 267.1557 CM + Li] *; 267.1532 calculated for CxaLHaoNß0ßLi.

C. Synthesis of DAla-Ala-QEt-TFA 31.4 g, 109 mmol, of the protected dipeptide was dissolved in 200 ml of methylene chloride and 66 ml of TFA was added. The resulting solution was allowed to stir for 30 minutes at room temperature and concentrated. The residue was coevaporated with 2? 200 ml of methylene chloride was dissolved in ether and separated in oil with the addition of excess hexanes. The solvent was decanted and the pumped the residue under high vacuum for 12 hours, to give 39.6 g (100% yield, contains residual TFA) of the desired TFA salt, as an orange oil. NMR with AH (DMSO-dβ) delta 1.16 (t, J = 7.0 Hz, 3 H), 1.28 (d, J «7.0 Hz» 3 H). 1.34 (d »J ss 7.0 Hz, 3 H); 3.86 (8 broad, ÍH); 4.07 (c, J = 7.0 Hz, 2 H), 4.26 (quintet, J = 7.0, 1 H), B.21 (8 broad, 3 H); 8.86 (d, J = 7.4 Hz, 1 H), MS (LRCI, CH ") m / z (relative intensity) 217 (5) CM-C3Hß} • «-, 189 (40) CM + H3-.

D. Synthesis of Boc-Ala-DAla-Ala-OEt To a solution of 20.1 g »77.2 mmol» of Boc-Ala-Ala-OH in 850 ml of DMF »was added 13.1 g» 85.4 mmol »of HOBT -H30 and 16.4 g »85.4 mmol» of EDC-HC1. To this solution was added 23.3 g »77.2 mimol» of DAl a-Al a-OEt-TFA »followed by 11.9 ml» 85.4 mmol »of TEA» and the resulting mixture was stirred for 12 hours later. The DMF was evaporated and the residue was dissolved in 300 ml of ethyl acetate and washed with 150 ml of 1M potassium bisulfate with 150 ml of water, with 150 ml of stined sodium bicarbonate and with 150 ml of brine. The ethyl acetate layer was dried in magnesium sulfate, filtered and concentrated to half the volume and the crystal was allowed to proceed. Filtration isolation produced 20.5 g (62% yield) of the desired tetrapeptide, as a white solid. NMR with AH (DMSO-dβ) delta 1.13 (d, J = 7.2 Hz, 3 H), 1.17 (two coinciding d, J = 7.0 Hz, 6 H). 1.25 (d »J - 7.4 HZ, 3 H). 3.91 - 4.30 (m.6 H), 6.87 (d.J = 7.0 Hz, 1 H), 7.92 (d.J = 6.3 HZ, 1 H), 8.07 (d »J = 7.3 Hz» 1 H) »8.09 (d »J = 6.6 HZ, 1 H); MS (HRFAB, NBA - Li) m / z = 437.2600 CM + LÍ *; 437.2588 calculated for CJt "H3 ^ N.« 0.yLi.

E. Synthesis of Boc-Al a-Al a-DAl a-Al a-OH A solution of 10.9 g was treated. 25.3 mmoles. from Boc- Al a-Al a-DA I a-Al a-OEt in 100 ml of methanol »with 20.0 ml» 50.0 mmol »of 2.5 M sodium hydroxide and left the resulting solution stirring for two hours at room temperature ambient. At that time, the pH of the solution was lowered to about 3 »with the addition of aqueous potassium bisulfate and the resulting mixture was extracted with 3 × 100 ml of ethyl acetate. The combined extracts were dried over magnesium sulfate and concentrated to give 6.8 g (67% yield of the desired acid) as a white solid NMR with AH (DMSO-dβ) delta 1.17 (d.J = 7.2 Hz. H) 1.20 (two coincident d, J = 7.1 Hz, 6 H) 1.28 (d, J = 1.3 Hz, 3 H), 1.38 (s, 9 H), 3.90 - 4.00 (m, ÍH). 4.17 - 4.30 (m.3) H); 6.903 (d »J = 6.7 HZ» 1 H), 7.96 (d, J - 6.7 Hz, 1 H), 8.04 (d, J = 7.4 HZ, 1 H), 8.07 < d, J = 7.8 Hz, 1 H); MS (HRFAB, NBA L) m / z = 409.2331 CM + LÍ3 - * -; 409.2353 calculated for CxtH3ON ^ 0 ^ Li.

F. Sinteßiß of Boc-Al a-Al a-DAla-Al a-DAla-OBzl To a solution of 6.5 g, 16.3 mmoles of Boc-Ala-Ala-DAla-Ala-OH in 180 ml of DMF, ß added 2.86 g, 18.7 mmoles, of HOBT-H.?0 and 3.58 g, 18.7 mmoleß, of EDC.HCl. The resulting solution was allowed to stir for 15 minutes at room temperature and treated with 6.57 g, 18.7 mmoleß "of the p-toluenesulfonate salt of DAla-OBzl and 2.6 ml» 18.7 mmoleß »of TEA. It was left to mix this mixture for 12 hours later. The DMF was evaporated and the residue was partitioned between 300 ml of ethyl acetate and 300 ml of water. The ethyl acetate layer was washed with 150 ml of potassium bisulfate 1 N. 150 ml of water. 150 ml of saturated sodium bicarbonate and 150 ml of brine. The ethyl acetate layer was then dried over magnesium sulfate, filtered and concentrated to give 9.0 g (100% yield) of the desired compound, as a white powder. NMR with AH (DMSO-dβ) delta 1.17 (d J = 7.3 Hz, 3 H), 1.21 (two coinciding d, J = 7.0 Hz, 6 H). 1.22 (d.J = 7.0 Hz, 3 H), 1.32 (d, J = 7.3 Hz, 3 H), 1.37 (8.9H), 3.90-4.09 (m, 1 H); 4.18-4.34 (m, 4 H); 5.13 (ABq, J «12.7 delta v as-10.5 HZ, Z H); 6.94 (d.J = 7.3 Hz, 1 H); 7.30 - 7.41 (m, 5 H), 7.97 (d, J = 7.0 Hz, 1 H), 8.10 - B.1B (m, 2 H); 8.25 (d.J = 6.9 HZ, 1 H); MS (HRFAB, NBA - Li) m / Z = 570.3140 CM + LÍ *; 570.3115 calculated for.

G. Synthesis of Ala-Ala-DAla-Ala-DAla-.HCl 10.4 g was dissolved. 18.7 mmoles. of Boc-Ala-Ala-DAla-Ala-DAIa-OEt in 225 ml of acetic acid and treated with 75 ml of concentrated hydrochloric acid. The solution was allowed to stir at room temperature for 14 hours thereafter. At this time, the reaction was concentrated, coevaporated with 50 ml of water and dried azeotropically by coevaporation with 2? 100 ml of toluene, to give 7.8 g (96% yield) of the deprotected pentapeptide hydrochloride, as a white powder. NMR with AH (D30) delta 1.29 - 1.39 (m.12H). 1.47 (d.J sß 7.0 Hz. 3 H), 4.06 (C, J = 7.0 Hz, 1 H), 4.18 - 1.38 (m, 4 H); MS (LRFAB, NBA -HCl) 374 CM + H3 - * -.

H. Synthesis of Cyclo- (A1a-Ala-DA1a-Ala-DA1a-) To a solution of 7.8 g, 19.0 mmol, of Ala-Ala-DAla-Ala-DAla-HCI in 2400 mL of DMF, at -40 ° C, 6.29 g, 22.8 mmoles of DPPA and sufficient TEA were added to adjust the pH to about 8, as measured by determination of spots in the reaction mixture on wet hydride paper). This mixture was allowed to stand at -23 ° C for 48 hours and at 8 ° C for 48 hours. During this time, the pH of the solution was again maintained at around 8, with periodic addition of TEA. At the end of this period, the reaction mixture was poured into 2400 ml of water and stirred with mixed bed ion exchange resin (1200 g) for several hours. The resin was mined and the filtrate was concentrated to a volume of about 100 ml. 500 ml of ether and ether were added by filtration of the precipitated white solid and washed with an additional 250 ml of ether. The solid was then triturated by stirring with 100 ml of THF for 12 hours (to remove the traces of DMF), filtered and made perfectly to produce 3.15 g (47% yield) of the desired cyclic peptide, as a white powder, fine. NMR with «-H (DMSO-d ,,,) delta 1.08-1.25 (m, 12 H); 1.24 (d.J = 7.3 HZ »3 H), 4.00-4.10 (m.h. H)» 4.26-4.30 (m, 2 H); 4.34 (c. J = /.2 HZ »1 H9» 4.41 (C. J = 7.6 Hz. 1 H), 7.58 (d, J = 7.9 HZ »1 H), 7.83 (d, J = 8.4 Hz, 1 H), 8.22 (d, J = 6.2 HZ, 1 H), 8.33 (d, J = 7.81, 1 H), 8.49 (d, J = 6.8 Hz, 1 H), MS (HRFAB, NBA - HCl) m / z 356.1989 (M + H) *; 356.1934 calculated for XßHMNβO (M + H) "4-.

I. Synthesis of (2S.5R, BS, llR, 14S) -pentamethyl-l »4,7,10,13-pentaazacyl-pentadecane To a stirred suspension of 3.10 g, 8.70 mmoles, of cyclo- (Ala-Ala-DAla- Ala-DAla-) in 70 ml of THF, at room temperature, was added 108 ml of a 1.0 M solution of lithium aluminum hydride in THF (108 mmoleß). The resulting mixture was stirred at room temperature for 2 hrs. And then heated to reflux for 16 h, subsequently. The mixture was then cooled to about -20 ° C and quenched with the dropwise addition of about 30 ml of saturated sodium sulfate. The resulting mixture was concentrated to a dry white powder, and that powder was triturated with 2? 150 ml of ether. The combined triturates were concentrated and recrystallized from acetonyl tri to give 1.10 g (44% yield) of the desired ligand as a white solid. NMR with * H (CDC13) delta 0.96 (d J = 5.2 Hz, 3 H), 1.00 (two matching d, J = 5.0 Hz, 6 Hz), 1.02 (two matching d, J = 5.0 Hz, 6 H); 1.02 (two matching ds »J = 5.0 HZ, 6 H), 1.30 - 1.55 (broad m 2 H), 1.85 - 2.15 (broad S 3 H); 2.05 - 2.19 (m.5 H>, 2.42 - 3.00 (complex m.12 H); MS (HRFAB, NBA-HC1) m / Z 286.3013 (M + H) *; 286.2971 calculated for XßH3"Nß-J. Synthesis of Chloride (III) he? Afluorophosphate dichloro- (2S »5R, BS .11R.14S) pentameti 1-1, 4, 7, 10.13-pentaazacic1opentadecano3 This complex was prepared in a completely analogous manner to that previously described in the example 3. After recrystallization of the crude yellow solid in ethanol, yellow crystals were obtained in a yield of 40% Analysis calculated for C ßH33NßCla? FeFβP: C »32.37; H. 6.34; N. 12.59 Found: C. 32.44; 6.30; N »12.40.

E EMPLO 5 KINETIC ANALYSIS PE Fü? Q DETENTION The kinetic analysis of stopped flow has been used to determine if a compuest can catalyze the dißmutation of superoxide (Riley, D. P .: Rivers)., W. J and Weiss »R. H Stopped-Flow Kinetic Analyzes for Monitoring Superoxide Decay in Aqueous Systems, Anal. Biochem. »196, 344-349 (1991). To obtain consistent and accurate measurements, all reactants were biologically clean and free of metal. To achieve this, all regulators (Calbiochem) were free biological regulators of metal, and were handled with utensils that had been washed first with 0.1 N HCl, and then with purified water, followed by a rinse in an EDTA 10 bath. "M, at pH 8, followed by rinsing with purified water and drying at 65 ° C for several hours, Dry potassium superoxide (Aldrich)" solutions were prepared in dry DMSO, inert argon, in a box Vacuum Atmospheres dried gloves, using dry glassware DMSO solutions were prepared immediately before each stopped flow experiment, a mortar and pestle was used to grind about 100 mg of solid, yellow potassium superoxide. The powder was ground with a few drops of DMSO and the suspension was transferred to a flask containing an additional 25 ml of DMSO The resulting suspension was stirred for half an hour and then filtered. This gave reproducible concentrations of about 2 mM superoxide in DMSO. These solutions were transferred to a bag of gloves under nitrogen, in sealed jars, before loading the syringe under nitrogen. It should be noted that the DMSO / solutions exceeded? They are extremely sensitive to water, heat, air and foreign metals. A fresh, pure solution has a very yellowish dye. Water for regulatory solutions was supplied from a domestic deionized water system, to a Barnstead Nanopure Ultrapure water system, 550 series, and then distilled twice, first in alkali potassium permanganate and then in a diluted EDTA solution. For example, a solution containing 1.0 g of potassium permanganate, 2 liters of water and additional sodium hydroxide, necessary to bring the pH to 9.0, was added to a two-liter flask equipped with a distillation head. solvent. This distillation will oxidize any trace of organic compounds present in the water.

The final distillation was carried out under nitrogen, in a 2.5 liter flask containing 1500 ml of water, from the first distillation, and 1.0 x 10 * M EDTA. This step will eliminate the remaining traces of metals from ultrapure water. To prevent the EDTA spray from volatilizing on the reflux arm towards the distillation head, the 40 cm vertical arm was packed with glass beads and wrapped with insulation. This system produces deoxygenated water that can be measured to have a conductivity of less than 2.0 nanohms / cm *. The dengue flow spectrometer system was designed and manufactured by Kinetic Instruments Inc. (Ann Arbor, MI, E.U.A.) and interfaced with a MAC IICX personal computer. The application program for the flow stopped analysis was provided by Kinetics Instrument Inc »and was written in QuickBasic» with MacAdiós actuators. Typical volumes of injector (0.10 ml of regulator and 0.006 ml of DMSO) were calibrated so as to mix a large amount of water over the DMSO solution. The actual ratio was approximately 19/1 »so that the initial concentration of superoxide in the aqueous solution was on the scale of 60 to 120 μM. Since the published extinction coefficient of superoxide in water at 245 nm is around 2250 M * - * cm- * (1) »an initial absorbance value of about 0.3-0.5» would be expected for a cell with 2 cm path length; and this was observed experimentally. Aqueous solutions were prepared to be mixed with the superoxide DMSO solution using 80 mM concentrations of Hepes buffer. pH 8.1 (pound acid + Na form). One of the reservoir syringes was filled with 5 ml of the DMSO solution while the other was filled with 5 ml of the aqueous buffer solution. The entire injection block, the mixer and the spectrometer were submerged in a circulating water bath, regulated with a thermostat, with a temperature of 21.0 ± 0.5 ° C. Before starting data collection for a superoxide decomposition, an average basic line was obtained by injecting several discharges of the regulator and DMSO solutions into the mixing chamber. These downloads were averaged and stored as the baseline. The first discharges to be collected during a series of operations were with aqueous solutions that did not contain catalyst. This ensures that each series of tests was free of counting and was not able to generate a decomposition of superoxide decomposition of the first order. If the decomposition observed for several discharges of the buffer solution were of second order, solutions of iron (II) complexes could be used. In general »the potential SOD catalyst was selected in a wide range of concentrations. Since the initial concentration of the superoxide when mixing the DMSO with the aqueous regulator was around 1.2 x 10 - ** M, it was wanted to use an iron (III) complex concentration that was at least 20 times lower than the superoxide of substrate Consequently, compounds with SOD activity were generally selected, using concentrations varying from 5? lO- "7 to 8? 10-* M. The data acquired from the experiment were imported into a suitable mathematical program (for example, Cricket Graph) so that normal analysis of kinetic data could be performed. for superoxide dissolution by the iron (II) complexes of Example 1-4, from the linear plot of the observed regime constants (kßBβ) against the iron (III) complex of iron. The kβB, ββ values of the linear absorbance graphs were obtained at 245 nm, against time, for the dismutation of the superoxide by the iron (III) complex. The ßß (M- ^ sec - * -) of the iron (III) complexes of Examples 1 to 4 are shown in Table I. The iron (III) complexes of the macrocyclic nitrogen-containing ligands in Examples 1 -4 ßon effective catalysts for the dismutation of the superego, as you can see from the kßak data in table I.

TABLE I Compound of kcat at pH 7.6, 21 ° C example No. (M-lsea-1) 1 1.06? 10 * - * 2 0.96? 10"" - 3 1.60? 10 ** 4 2.94? 10 ** '

Claims (12)

NQVEDAP PE THE INVENTION CLAIMS

1. - Pharmaceutical composition in the form of two units, useful for dismutar superoxide, characterized in that it comprises: (a) a therapeutic or prophylactically effective amount of a complex represented by the formula:

where R, R ", Rx, Rtx, Ra, R» 3, R3, R3, R ^, R »^, Rβ, R» ß, Rβ », ß 'Rt» Rtt »Rβ» R, «» R * and Rf are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenyl, alkylcycloalkyl, alkenyl, cycloalkyl, alkylcycloalkenyl, alkenyl, cycloalkenyl, heterocyclic, aryl, and aralkyl. and radicals attached to the alpha carbon of alpha-amino acids, or Rx or R'x and R3 or Rra. R3 or Rta and R ^ or R, ^. Rß or R "ß and R« or R'ß 'Rt or Rtt and Rβ ° R '"and R" ° R, ß and Rf "together with the carbon β atoms to which a βß" independently form a partially saturated or unsaturated saturated cyclic having 3 to 20 carbon atoms; or R or Rf and R, O R ^. and R3 O R'a, R3 OR * 3 and R ^ O R '^, Rβ OR,' ß and Rβ or R'ß, R-, or R '., and R. or R'ß and R "or R'ß "together with the carbon atoms to which they are attached, independently form a nitrogen-containing heterocycle, having from 2 to 20 carbon atoms, provided that, when the nitrogen-containing heterocycle is an aromatic heterocycle that it does not contain hydrogen bound to nitrogen, hydrogen is fixed to nitrogen in the above formula, nitrogen also is present in the macrocycle, and R groups attached to the same carbon atoms of the macrocycle are absent; wherein X, Y and Z are ligands selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, enol, oxygen, peroxo, hydrperoxo, alkyloperoxide, aryl peroxide or ammonia. ali lamino arylamino. heterocycloalkyl, heterocycloalkam, amine oxides, hydrazine, alkylhydrazine, aryhydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkylenitrile, ary triol, alkyl isoni tri, arylsonitrile. nitrate, nitrite, azido. alkylsulfonic acid. arylsulfonic acid. alkyl sulfoxide, aryl sulfoxide, alkylaryl sulfoxide. alkylsulfenic acid. Ißulfenic acid, alkylsulfinic acid, arylsulfinic acid, aluminum alkylcarboxylic acid, 1-halocarboxylic acid, alkyl thiol-thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkylcarboxylic acid (such as acetic acid, trifluoroacetic acid) , acid or alkali), arcarboxylic acid (such as benzoic acid, phthalic acid), urea, alkyl urea, ar urea, alkyl aryl urea, thiourea, alkyltourea, arylthiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thioesulfate, thiosulphite, hydrophite. Alkylphosphine, Alkylphine, Alkyl Phosphine Oxide, Arylphosphine Oxide, Alkyl Ifosphine Oxide, Alkyl Phosphine Sulphide, Arylphosphine Sulfide, Alkylolophosphine Sulphide. alkyl-phosphonic acid. Aryosophonic acid. Ionic alphosphate acid. aric acid Ifoßf ínico. alkylphosphinous acid, ari Ifosfinoso acid, phosphate »thiophosphate» phosphite »pyrophosphite» triphosphate »acid phosphate» diacid phosphate »alkylguanidino, arylguanidino. alkylaryl 'guanidi no' alkyl carbamate »aryl carbamate» alkylaryl carbamate »alkyl thiocarbamate» aryl thiocarbamate »alkylaryl thiocarbamate, alkyl dithiocarbamate. aryl dithiocarbamate »alkylaryl dithiocarbamate» bicarbonate, carbonate »perchlorate» chlorate »chlorite» hypochlorite »- perbroraate. bromate. little joke hypobromite. tetrahalomanganate. tetrafluoroborate »hexafluorophosphate. hexafluoroantimonate, phophosphite »iodate, periodate. metaborate »tetraaryl borate, tetraalkyl borate, tartrate, salicylate, succinate, citrate. ascorbate, saccharine born. amino acid, hydroxamic acid, thiotosylate and anions of ion exchange resins, or their corresponding anions; or X, Y and Z are independently fixed to one or more of the "R" groups and n eß an integer from O to i; and (b) a pharmaceutically acceptable non-toxic carrier, adjuvant or vehicle. 2. Composition according to claim 1 further characterized in that at least one of R »R» »RX» R'x, Ra »R'a, R3» R'3 »> R '»RB» R'ß' R «» R, «'R-?' R, v »ß 'R, ß' Rβ and R, ß are alkyl or β-sulphite alkyl with -0Rxo or -R ^ or R. wherein Rxo and Rxx are independently hydrogen or alkyl; and the remaining "R" groups are hydrogen or are part of a saturated, partially saturated or unsaturated cyclic. or they are part of a nitrogen-containing heterocycle. 3.- Composition in accordance with the claim

2. characterized further because at the menoß doß of R. R * »RX, R '» Ra »R'a» R3 »R'3» R ^ »R' ^» Rß »R'ß 'R *' R * ß» Rr »R, t» Rβ »R'ß '" and f * "are alkyl or alkyl substituted with -ORXO or -NRxoRxx" and the remaining "R" groups are hydrogen. 4.- Composition in accordance with the claim

1 »characterized in that at least one of R or R'x and Ra or R'a» R3 or R * 3 and R »,,, Rß or R» a and Rß or R'ß, R7 or R and Ra or R 'ß and R' or R'β and R ', together with the carbon atoms loe which are attached' form a saturated cyclic 'partially saturated or unsaturated having from 3 to 20 carbon atoms; and the "R" -restricting groups are hydrogen, alkyl or alkyl substituted with -ORXO or -NRxoRxx groups or are part of a nitrogen-containing heterocycle; wherein R x and R are independently hydrogen or alkyl. 5.- Composition in accordance with the claim

4 »further characterized because the remaining" R "groups are hydrogen, alkyl or alkyl substituted with -0Rxo groups or -NRxoRxx groups. 6.- Composition in accordance with the claim

5, further characterized by at least one of R or R »and Ra or R'a, R3 O R'3 and R ^ or R» ^, Rβ? Rtß and Rß? R »ß, R ^ or R '^ and

Rß or R'ß and ° Rt »and R ° RT 'Ju to the carbon atoms to which they are attached, is a group ciel ohe? An. 7.- Composition in accordance with the claim

6. further characterized because at least two of R or R'x and Ra or R'a. Ra or R * a and R ^ or R '^. Rß or R »ß and R or R * ß. R ^ or R'-, and

R »° Rfß and Rß ° R'ß and R ° R * 'together with the carbon atoms to which they are attached, are groups ciel ohe? An. 8.- Composition in accordance with the claim

1, further characterized by at least one of R or R 'and R or R', Ra or R * a and R3 or R'3 »R ^ or R '^ and Rm or Rfβ» R «° R, ß and R and Rβ or R'ß and R or R, "together with the carbon atoms to which they are attached, are linked to form a nitrogen-containing heterocycle; and the remaining "R" groups are hydrogen, alkyl or alkyl substituted with -ORXO groups or -NRxoRxx groups or are part of a saturated or partially saturated or unsaturated cyclic; wherein R x β and R x are independently hydrogen or alkyl. 9.- Composition in accordance with the claim

1 »further characterized in that X» Y and Z are independently selected from the group consisting of halogrin anions »organic acid, nitrate and bicarbonate.

10. - The use of a complex of claim 1. to prepare a medicament for preventing or treating a disease or disorder that is mediated, at least in part, by superoxide.

11. The use according to claim 10. further characterized in that the disease or alteration are selected from the group consisting of reperfusion damage to an ischemic organ, surgically induced ischemia, inflammable bowel disease »rheumatoid arthritis» osteoarthritis, psoriasis, rejection of organ transplantation, radiation-induced damage »injuries and tissue damage, induced by oxidant, atherosclerosis. thrombosis »platelet accumulation» metastasis, attack »acute pancreatitis» insulin dependent diabetes mellitus »disseminated intravascular coagulation» fat embolism »respiratory difficulties in adults and children» and carcinogenesis.

12. The use according to claim 11. further characterized because the disease or alteration is selected from the group consisting of reperfusion damage to an ischemic organ »surgically induced ischemia» attack, atherosclerosis and inflammable bowel disease.

FIELD ANNEX FIELD Í571 SUMMARY OF THE INVENTION

Mimics of low molecular weight of superoxide dismutase

(SOD), represented by the formula:

wherein R, R ', R1 # R'lf R2, R'2' R3 > R # 3 'R4' R, 4 > R5 'R, 5- R6' R'g, R7, R '?, Rs, R's »R9 and R'g and X, Y, Z and n are as defined herein, useful as therapeutic agents for inflammatory disease states and inflammatory alterations, ischemic / reperfusion damage, attacks, atherosclerosis, inflammable bowel disease and all other lesion conditions or tissue damage, induced by oxidant.

P98 / 932F