MXPA97003932A - Meso-monoyodo-substitute tetramacrocyclic compounds and methods for manufacturing and using losmis - Google Patents

Abstract

The present invention relates to a meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): wherein: each of A to D is independently a ring containing nitrogen of 5 elements, having the necessary elements to complete a porphyrin, chlorine, bacteriochlorin or isobacteriochlorin nucleus, R1 to R8 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or an ester group of the acid, keto, hydroxy, nitro, amino, or a group which, taken together with another ring, ring substituent or meso-substituent, it forms a ring of 5 or six elements, fused, and each of S1 to S3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, a substituted aromatic ring or unsubstituted, or a substituted or unsubstituted heterocyclic ring. A method for synthesizing the compound comprises the step of iodinating a corresponding unmetallated, non-halogenated tetramacrocyclic compound followed by the metation. The compound of the invention is an intermediate capable of binding or coupling with an alkyl to achieve or obtain a mono-mesoalkynyl compound desired

Description

TETRAMACROCYCLIC COMPOUNDS ME30-MONOYODO- SUBSTITUTES AND METHODS TO, MANUFACTURE AND USING THEMSELVES Field of the invention The present invention relates to certain eso-monoiodo-substituted macrocycles, to their preparation and to their use in the synthesis of macro-cyclic compounds that-monoalkynyl. In particular, the invention relates to the iodination of meso-unsubstituted tetramaorooiols which may or may not be substituted in some or all of the three remaining meso positions with an alkyl or cycloalkyl group, an aromatic ring, or a heterocyclic compound. Many of these compounds are useful photosensitizers, desirable in the field of photodynamic therapy ("PDT") to mediate the destruction of unwanted cells or tissues or other undesirable materials by irradiation. Others are also valuable intermediaries for making other such photosensitizers.

Ref. 24777 Background of the Previous Technique In the field of PDT, several tetrapyrrolic macrocycles, such as purpurins, chlorins, bacteriochlorins, phthalocyanines and benzoclorins, have shown the ability to both locate a tumor site and absorb light to form an activated state in response to light. . The tetramacrocycles then exhibit a cytotoxic effect on cells or other tissues in which they are localized when they are irradiated at the appropriate wavelength. In order to elicit the depth of the desired toxic effect within a tissue of the subject, however, it is necessary to use photosensitizers having high absorption coefficients at wavelengths longer than 650 nm, where the tissues of the body are more transparent to light . See Sternberg et al., "An Overview of Second Generation Drugs for Photodynamic Therapy Including BPD-MA (Benzoporphyrin Derivative)," Photodynamic Therapy and Biomedical Lasers, 470-4 (Spinelli et al., 1992). In addition, the binding of the photosensitizer with certain biological materials may make it possible for the photosensitizer to "reside" more selectively with respect to target tissue, causing minor damage to surrounding normal tissues.

Tetra acrocyclic compounds, substituted with meso-alkynyl, have been recognized as compounds having potentially valuable electrochemical and optical spectrum properties. Lin et al., Science, 264, 1105-11 (1994), and Arnold et al., J. Chem. Soc., Chem. Commun. , 2131-32 (1994). Because of this, it has been interesting to develop efficient synthetic routes for these compounds. Previous methods to provide meso functionalization, for example, formylation and nitration, have required "the use of strict or severe conditions capable of altering or destroying other functional groups on the tetramacrocyclic nucleus. a single type of functional group on the tetramacrocyclic nucleus, which must subsequently be manipulated, frequently in multi-step procedures, to have access to other useful substituents The 5,15-di-bromination of the tetramacrocyclic compounds has been described by DiMagno et al., "Facile Elaboration of Porphyrins via Metal-Mediated Cross-Coupling", J. Qrq. Chem., 58, 5983-93 (1993), and DiMagno et al., "Catalytic Conversion of Simple Haloporphyrin into Alkyl -, Aryl-, Pyridil-, and Vinyl-Substituted Porphyrins ", J. Am. Chem. Soc., 115, 2513-15 (1993) .However, metal-mediated binding reactions on porphyrins Brominated materials have typically required the use of Schlenk inert atmosphere techniques, high pressures and temperatures, and sensitive Pd (0) reagents. In addition, the non-porphyrin moiety of the couple or the joint is itself a relatively unstable zinc or tin organometallic compound, which must be prepared separately. In addition, although bromatizations and chlorinations have been carried out successfully for many porphyrins substituted differently, iodizations have proven to be problematic, either producing unstable products or requiring the activation of the porphyrin nucleus with highly toxic mercury salts3. When the iodinated porphyrin compounds have been prepared and characterized, the iodine substituents have typically been in the ß position. See, for example, Zhou et al., "Synthesis of ß-Octasubstituted Sterically Bulky Porphyrins by Suzuki Cross Coupling", 1 J. Chem. Soc, Perkin Trans. 1, 2519-20 (1994). The tetracycrocyclic pteso-iodophenyl compounds have also recently been prepared by halogenation of the meso-phenyl groups on a tetramacrocyclic core. Lindsey et al., "Porphyrin Building Blocks for Modular Construction of Bioorganic Model Systems", Tetrahedron, 90:30, 3941-68 (1994), and Ali et al., "Synthesis of ß-Substituted Porphyrin Using Palladium Catalysed Reactions", Tetrahedron, 50: 11933-44 (1994). However, none of these workers has taught the direct meso-iodination, instead of ß-iodination, of a tetra acrocycle without a phenyl ring involved in the reaction. In the description of initial attempts to iodize "porphyrin", "octaethylporphyrin" and "tetraphenylporphyrin" by Samuels et al., "Halogenation of Porphin and Octaethylporphin", J. Chem. Soc., 145-47 (1968), the polyiodinated product resulting could not be isolated and / or purified successfully. In addition, the positions of the iodine substituents, when present, may not be determined. Minnetian et al., "New Syntheses and Reactions of Some Halogenated Porphyrins ", J. Org. Chem., 54: 5567-74 (1989), describes the preparation of a β-iodo porphyrin compound (page 5568) and the preparation of a meso-chloro porphyrin compound (page 5570). However, no meso-iodination was observed (page 5571) In addition, Minnetian et al., Teaches that the halogenation site should be determined by the size and reactivity of the halogen in question. to be favored only by smaller halogens, such as chlorine, while larger halogens, such as bromine and iodine, should favor only ß-halogenation.Ali et al., "Synthesis of ß-Substituted Porphyrin Using Pailadium Catalysed Reactions ", Tetrahedron, 50: 11933-44 (1994), describes, among other things, the attempted preparation of a mono-iododeuteroporphyrin IX dimethyl ester, which is to be used in a subsequent binding reaction with an alkyne. Without emba However, only an isomeric mixture of the β-substituted products (3- and 8-monoiodates) were obtained in the company of a 3, 8-di-iodinated product. No meso-monoiodation was reported. Despite these teachings in the art to the contrary, it has now been found that meso-monoiodination of a demetallated or demetalated tetramacrocycle can be effected directly with the use of a suitable iodinating agent under advantageously mild conditions, even when there are no other meso. -substitute or ß, ß '-substitute - present to block the competent side reactions. The resulting meso-rnonoiod-tetramacrocycles are reasonably pure, whereby desirably high yields are also provided. In addition, a wide range of different substituents can be introduced directly onto the tetramacrocyclic ring by means of a common reaction of the meso-monoiodo compound with a suitable alkynyl compound. The mesoalkynyl substituent can be broadly derivatized, and the resulting substituents can include biologically active groups, such as testosterone and estradiol which are frequently susceptible to damage caused by elevated temperatures and / or pressures. Accordingly, to prevent or avoid the total synthesis of the tetramacrocyclic system, a facilitated access is allowed to a wide variety of analogues from a pre-formed, conveniently common tetramacrocycle. When the meso-alkynyl tetramacrocycle contains an aryl ring, such as a phenyl group, the ability to further derivate these compounds provides an opportunity for a fine tuning of the pharmacokinetic and dynamic characteristics of the compounds to an even greater extent. Accordingly, a number of related meso-substituted chlorines and bacteriochlorines can be made, which exhibit particularly desirable characteristics as PDT agents, such as batochromically displaced Q bands and increased amphiphilicity.

Description of the invention In accordance with the present invention, novel meso-monoiodo-substituted tetramacrocyclic compounds having the formula (I) have been prepared: wherein: each of A to D is independently a ring containing nitrogen, of 5 elements, having the necessary elements to complete a nucleus of porphyrin, chlorine, bacteriochlorin or isobacteriochlorin; Ri to R8 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or an acid ester group, keto, hydroxy, nitro, amino, or a group which, taken together with another ring, substituent of ring or meso-substituent, forms a ring with 5 or 6 elements, fused; and each of S1 to S3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heterocyclic ring.

In addition, a method for efficiently synthesizing the compounds of the formula has been found (I) Specifically, in the invention, a method for making a compound having the formula (I) comprises the steps of treating a tetramacrocycle having the formula (II): wherein A to D, Ri to Rβ, and S1 to R3 are as described above, with an iodinating agent to form the tetramacrocyclic compound of the formula (I). In addition, a method for manufacturing the corresponding meso-alkynyl tetramacrocyclic compound having the formula (III): C I I ID wherein M is a metal selected from the group consisting of Ni (ID, Cu (II), Zn, Sn, Ge, Si, Ga, Al, Mn (III), Gd (III), In and Tc; A to D, Ri to R8, and S1 to S3 are the same as described above, and Rg is an organometallic radical, a substituted or unsubstituted alkyl group having from 1 to 30 carbon atoms, an aromatic ring, a ring heterocyclic, or a biological substrate, comprises the steps of: a) treating a tetramacrocyclic compound having the formula (II), as described above, with an iodating agent to form the corresponding meso-monoiodo-substituted compound of the formula (I) ) b) metalar the meso-iodo-substituted compound to form the corresponding melamine compound, and c.alkynylate the metallated compound in the presence of an alkyne having the formula HCsC-R9 to give the meso-alkynyl tetramacrocyclic compound of the formula (III).

Brief Description of the Drawings The present invention will be understood more clearly by reference to the following drawings, in which: Figure 1 shows the electronic absorption spectrum for 10-iodo-5, 15-diphenylporfinine.

Figure 2 shows the electron absorption spectrum for zinc 10-iodo-5, 15-diphenylporphyrin. Figure 3 shows the electronic absorption spectrum for 10- (4-hydroxy-l-butynyl) -5,15-diphenylporphyrin. Figure 4 shows the electronic absorption spectrum for 10- (2-phenyl-1-ethynyl) -5, 15-diphenylporphyrin. Figure 5 shows the electronic absorption spectrum for 10- (3,3 '-dietoxy-1-propynyl) -5,15-diphenylporphyrin. Figure 6 shows the > electronic absorption spectrum for 10- (2-trimethylsilyl-1-ethynyl) -5, 15-diphenylporphyrin. Figure 7 shows the electronic absorption spectrum for 10- (2-testosterone-l-ethynyl) -5,15-diphenylporphyrin. Figure 8 shows the electronic absorption spectrum for 10- (2-estradiol-l-ethynyl) -5,15-diphenylporphyrin. Figure 9 shows the electronic absorption spectrum for 10- (1,7-octadiinyl) -5,15-diphenylporphyrin.

Ways to Carry Out the Invention The meso-monoiodo-substituted tetramacrocyclic compounds of the invention have the formula (I), as described and shown above. Each of A to D can independently be any ring containing nitrogen, of 5 elements, which has the necessary elements to complete the nucleus of porphyrin, chlorine, bacteriochlorin or isobaoterioolorin, such as those having the structures: Preferably, however, each ring, A to D, has one of the two above structures. R'i to Rβ can be any of a large number of ring substituents, provided that they do not interfere with the iodination, metallation or bonding reactions described above. Preferably, Ri to R8 are independently a hydrogen atom; a lower alkyl group, such as methyl, ethyl, n-propyl, isopropyl, t-butyl and n-pentyl; a lower alkyl carboxylic acid, such as formyl, carboxymethyl, carboxyethyl, carboxy-n-butyl, carboxy-sec-butyl, carboxy-n-hexyl; an ester group of carboxylic acid, such as the groups of -CH2CH2COOCH3, -CHCH2COOCH2CH3, -CH2CH (CH3) C00CH2CH3, -CH2CH2CH2COOCH2CH2CH3, CH2CH (CH3) 2COOCH2CH3; keto hydroxy; nitro; Not me; or similar. In addition, Ri and R2, R3 and R »R5 and e. or R and R8 can be taken together with the other ring, ring substituent or meso-substituent to form a fused 5 or 6 element ring. The ring of 5 or 6 elements fused, thus formed, can be any ring of 5 or 6 elements, saturated or unsaturated, carbocyclic or heterocyclic, which does not interfere with the iodation, metallation or binding reactions of the invention. Examples of such rings include cyclopentane, furan, thiophene, pyrrole, isopyrrole, 3-isopropyl pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2-dithiol, 1,3 -diol, 1, 2, -oxatiol, isoxazole, oxazole, thiazole, isothiazole, 1,2, 3-oxadiathiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1, 2, 5-oxathiazole, 1,3-oxathiol, benzene, cyclohexane, 1,2-pyran, 1,4-pyran, 1,2- pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin (dihydro form), pyridine, pyridazine, pyrimidine, pyrazine, piperazine, 1,3,5-triazine, 1,2,4-triazine, 1, 2, 4-oxazine, 1,3,2-oxazine, o-isoxazine, 1, 2, 5-oxathiazine, 1,4-oxazine, p-isoxazine, 1,1,6-oxathiazine, 1, 3, 5, 2-oxadiazine, morpholine, azepine, oxepin, tiepine, 1, 2, 4-diazepine, and the like. Preferably, when R1 and R2, R3 and R4, R5 and β or R and Re, form a ring of 5 to 6 elements, fused, the ring is a ring of 6 elements. More preferably, when Ri and R2, R3 and R. »R5 and Re» or R7 or Rß, form a ring, it is a carbocyclic ring - of 6 elements, ie, a benzene ring. In a particularly preferred embodiment, Ri to Rβ are independently hydrogen, methyl, ethyl, or lower alkyl esters, more preferably they are hydrogen, methyl or ethyl. In still another preferred embodiment, A to D and Ri to R8 have the necessary elements to make or manufacture a core of porphyrin, chlorine, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin. Sx to S3 are the same or different and can be H, any of a large number of substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings or substituted or unsubstituted heterocyclic rings. When one or more of S1 to S3 is an alkyl group, they preferably have in an approximate form from 1 to 18 carbon atoms, more preferably in an approximate form of 1 to 12 carbon atoms and, even more preferably, in an approximate form. -6 carbon atoms. Examples of typical alkyl groups are methyl, ethyl, isopropyl, sec-butyl, tert-butyl, n-pentyl and n-octyl. When one or more of S1 to S3 is an alkyl group, they may be substituted or unsubstituted with any group that does not interfere with other reactions of the invention, such as the iodation reaction. For example, when one or more of S1 to S3 is an alkyl group, they may be substituted by a halogen atom, such as fluorine, chlorine or bromine; a hydroxy group, such as in pentoses and hexoses; thiol; a carbonyl group, such as when the alkyl group is an aldehyde, ketone, carboxylic acid (eg, a fatty acid) or an ester or amide; a primary, secondary, tertiary or quaternary amino group; nitrile; a phosphate group; a sulfonate group; or other similar groups. When one or more of S1 to S3 is a cycloalkyl group, it preferably contains from about 3 to about 7 carbon atoms. Examples of typical cycloalkyl groups include cyclopropyl, cyclohexyl, and cycloheteroalkyl, such as glucopyranose or fructofuranose sugars. When one or more of S1 to S3 is a cycloalkyl group, they may be substituted or unsubstituted with any group that does not interfere with the iodation reaction. For example, when one or more of S1 to S3 is a cycloalkyl group, they may be substituted by any of the same substituents described above for the case when one or more of S1 to S3 is an alkyl group. When one or more of S1 to S3 is an aryl group, it preferably contains in an approximate form from 5 to 12 carbon atoms, optionally containing one or more rings that are fused to the existing conjugated porphyrin ring structure. Examples of suitable aromatic rings include phenyl, naphthyl, anthracenyl and the like. Examples of useful heterocyclic rings include furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2-dithiol, 1, 3-dithiol, 1, 2, 3-oxathiol, isoxazole, oxazole, thiazole, isothiazole, 1,2, 3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1, 3, 4 oxadiazole, I, 2, 3, 4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole, 1,2-dioxazole, 1,2-dioxazole, 1, 3, 4 -dioxazole, 1,2, 5-oxathiazole, 1,3-oxathiol, benzene, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1 , 3-dioxin, pyridine, N-alkyl pyridinium, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1, 2,4-triazine, 1,2,3-triazine, 1,2,4-oxazine, 1, 3,2-oxazine, 1, 3, 6-oxazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1, 2, 5-oxathiazine, 1,4-oxazine, o-isoxazine, p- isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine, 1,4,2-oxadiazine, i, 3, 5, 2-oxadiazine, azepine, oxepine, tiepine, 1,2,4-diazepine, indeno, isoindene, benzofuran, isobenzofuran, thionaphtene, isotion aftene, indole, indolenine, 2-isobenzazole, 1,4-pyrindine, pyrazole [3,4-b] -pyrrole, isoindazole, indoxazine, benzoxazole, anthranil, naphthalene, 1,2-benzopyran, 1,2-benzopyrone, 1 , 4-benzopyrone, 2, 1-benzopyrone, 2,3-benzopyrone, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, naphthyridine, pyrido [3,4-b] -pyridine, pyrido [3, 2-b] -pyridine, pyrido [3,4-b] -pyridine, 1,3, 2-benzoxazine, 1, 4, 2-benzoxazine, 2,3, 1-benzoxazine, 3, 1,4-benzoxazine, 1,2-benzisoxazine, anthracene, phenanthrene, carbazole, xanthene, acridine, purine. In another modality, at least one of S1 to S3 has the structure: wherein X, Y, Z, X ', Y' and Z 'may be any of a large number of substituents and are generally used to "fine-tune" the biological activity, biodistribution, absorption and characteristics of clearance or evacuation, and the physical properties of the desired product. One way in which this can be done is by selecting the substituents such that the compound of the formula (I) or (II) is an amphiphilic molecule. By "amphiphilic" is meant that the molecule becomes more asymmetric, such as (1) having both (a) a water-soluble region, highly polar, and (b) a water-insoluble, highly hydrophobic region; (2) having both (a) a non-ionic region and (b) an ionic region; or (3) having both (a) an anionic portion and (b) a cationic portion. However, it should be noted that the invention also includes meso-trisubstituted tetramacrocyclic compounds having substantially or exactly identical aryl or heterocyclic substituents.

In addition, any chosen aryl or heterocyclic meso-substituent should also not have any adverse effect on the ability of the compound to undergo the iodination step or other reactions used to prepare the compounds of the invention.

Preferably, X, X ', Y, Y' and Z are independently (1) hydrogen; (2) halogen, such as fluoro, chloro, iodo and bromine; (3) lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl and similar groups; (4) lower alkoxy, such as methoxy, ethoxy, isopropoxy, n-butoxy, t-pentoxy and the like; (5) hydroxy; (6) carboxylic acid or acid salt, such as -CH2COOH, -CH2COO-Na +, -CH2CH (Br) COOH, -CH2CH (CH3) COOH, -CH (Cl) -CH2-CH (CH3) -COOH, -CH2 -CH2-C (CH3) 2 -COOH, -CH2-CH2-C (CH3) 2 -COO ~ K \ -CH2-CH2-CH2-CH2-COOH, C (CH3) 3 -COOH, CH (Cl) 2 -COOH and the like; (7) carboxylic acid esters such as -CH2CH2COOCH3, CH2CH2COOCH2CH3, -CH2CH (CH3) COOCH2CH3, -CH2CH2CH2COOCH2CH2CH3, -CH2CH (CH3) 2COOCH2CH3, and the like; (8) sulfonic acid or acid salt, for example, salts of group Y and group II, ammonium salts, and organic cationic salts such as alkyl and quaternary ammonium salts; (9) an ester of sulfonic acid, such as methyl sulfonate, ethyl sulfonate, cyclohexyl sulfonate, p-tosylate, o-tosylate and the like; (10) phosphoric acid, phosphate or phosphate ester, such as O-ethyl phosphate, 0-O-diethium phosphate, or O-ethyl phosphonic acid; (11) amino, such as unsubstituted primary amino, methylamino, ethylamino, n-propylamino, isopropylamino, 5-butylamino, sec-butylamino, dimethylamino, trimethylamino, diethylamino, triethylamino, di-n-propylamino, methylethylamino, dimethyl-sec- butylamino, 2-aminoethanoxy, ethylenediamino, 2- (N-methylamino) heptyl, cyclohexylamino, benzylamino, phenylethylamino, anilino, N-methylanilino, N, N-dimethylanilino; N-methyl-N-ethylanilino, 3,5-dibromo-4-anilino, p-toluidino, diphenylamino, 4,4'-dinitrodiphenyla and the like; (12) cyano; (13) nitro; (14) a biologically active group; or (15) any other substituent that increases the amphiphilic nature of the compound of the formula (I) or (II). The term "biologically active group" can be any group that selectively promotes the accumulation, elimination, agglutination rate, or the tightness of the agglutination in a particular biological environment. For example, a category of biologically active groups are substituents derived from sugars, specifically, (1) aldoses such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lixose, allose, altrose, glucose, mannose, gulose, idosa, galactose, and talose; (2) ketoses such as hydroxyacetone, erythrulose, rebulosa, xylulose, sicosa, fructose, sorbose, and tagatose; (3) pyranose such as glucopyranose; (4) furanoses such as fructofuranose; (5) O-acyl derivatives such as penta-O-acetyl-a-glucose; (6) 0-methyl derivatives such as methyl a-glucoside, methyl β-glucoside, methyl α-glucopyranoside, and methyl-2,3,4,6-tetra-O-methyl-glucopyranoside; (7) phenylosazones such as glucose phenylosazone; (8) sugar alcohols such as sorbitol, mannitol, glycerol, and myo-inositol; (9) sugar acids such as gluconic acid, glucaric acid and glucuronic acid, d-gluconolactone, d-glucuronolactone, ascorbic acid, and dehydroascorbic acid; (10) Phosphoric acid esters such as 1-phosphoric acid of a-glucose, 6-phosphoric acid of a-glucose, 1,6-diphosphoric acid of ocfructose, and 6-phosphoric acid of α-fructose; (11) deoxy sugars such as 2-deoxy-ribose, rhamnose (deoxy-omeose), and fucose (6-deoxy-galactose); (12) amino sugars such as glucosamine and galactosamine; muramic acid and neuraminic acid; (13) disaccharides such as maltose, sucrose and trehalose; (14) trisaccharides such as raffinose (fructose, glucose, galactose) and melezitose (glucose, fructose, glucose); (15) polysaccharides (glycans) such as glucans and mannans; and (16) storage polysaccharides such as α-amylose, amiloptine, dextrins, and dextrans. The amino acid derivatives are also biologically useful active substituents, such as those derived from valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, alanine, arginine, aspartic acid, cystine, cysteine, glutamic acid, glycine, histidine, proline, serine, tyrosine, asparagine, and glutamine. Peptides are also useful, particularly those known to have affinity for specific receptors, for example, oxytocin, vasopressin, bradykinin, LHRH, thrombin and the like. Another useful group of biologically active substituents are those derived from nucleosides, for example, ribonucleosides such as adenosine, guanosine, cytidine, and uridine; and 2'-deoxyribonucleosides, such as 2'-deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine. Another category of biologically active groups that is particularly useful is any ligand that is specific for a particular biological receptor. The term "ligand specific for the receptor" refers to a portion that binds to a receptor on cell surfaces, and therefore contains contours and charge configurations that are complementary to those of the biological receptor. The ligand is not the receptor itself, but a complementary substance to it. It is well understood that a wide variety of cell types have specific receptors designed to bind hormones, growth factors, or neurotransmitters. However, although these ligand-specific embodiments for receptors are known and understood, the phrase "ligand specific for a receptor", as used herein, refers to any substance, natural or synthetic, that specifically binds to a receptor. Examples of such ligands include: (1) steroid hormones, such as progesterone, estrogens, androgens, and adrenal cortical hormones; (2) growth factors, such as epidermal growth factor; the growth factor of the nerves, the growth factor of the fibroblasts, and the like; (3) other protein hormones, such as human growth hormone, parathyroid hormone, and the like; and (4) neurotransmitters, such as acetylcholine, serotonin, dopamine, and the like. Any analogue of these substances that also subsequently bind to a biological receptor are also included. Particularly useful examples of substituents which tend to increase the amphiphilic nature of the compound of the formula (I) include: (1) long chain alcohols, for example, -C? 2H24-OH wherein C12H24 is hydrophobic; (2) fatty acids and their salts, such as the sodium salt of the oleic acid of the long-chain fatty acid; (3) phosphoglycerides, such as phosphatidyl acid, phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol, phosphatidyl 3'-0-alanyl glycerol, cardiolipin, or phosphatidyl choline; (4) sphingolipids, such as sphingomyelin; and (5) glycolipids, such as glycosyl diacylglycerols, cerebrosides, cerebroside sulfate esters or galgliosides. In a preferred embodiment, X, X ', Y, Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid or acid salt, sulphonic acid, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z 'is hydrogen or lower alkyl. In another embodiment, X, Y, X 'and Y' are each hydrogen, and Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid, carboxylic acid ester, acid ester sulphonic (especially aromatic sulfonic acid ester), nitro, amino (especially lower alkyl amino), cyano, and a biologically active group. In yet another embodiment, X, Y, Z, X 'and Y' are selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, methoxy, hydroxy, OR where R is an alkyl group or an acid group fatty having from 6 to 18 carbon atoms, fluoro, chloro, iodo, bromo, -C (0) -0CH3, cyano, nitro, or a specific ligand for a biological receptor. In a further preferred embodiment, X, X ', Y and Y' and Z are selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid, sulfonic acid or acid salt, nitro, amino, cyano, and a biologically active group. In still another preferred embodiment, at least one of X, Y, Z, X 'and Y' is a biologically active group or a substituent that increases the amphiphilic nature of the molecule. In a particularly preferred embodiment, S1 to S3 are selected from the group consisting of phenyl, naphthyl, pyridinyl, pyridinium salts of N-lower alkyl, indolyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, indolizinyl, furanyl. , thiophenyl and steroids. Even more preferably, S1 to S3 are identical. A particularly preferred specific example of the tetramacrocyclic meso-monoiodo compounds of the invention is: The process for making the meso-monoiodo compounds of the invention comprises treating a tetramacrocycle of the formula (II) with an appropriate iodinating agent. The starting tetramacrocycle of the formula (II) for this reaction can be prepared by any of a number of standard procedures. Examples include techniques such as: (1) Appropriately substituted pyrrole and aldehydes can be prepared by the Adler method, according to Adler et al., "A Simplified Synthesis for meso- Tetraphenylporphyrin", J. Org. Chem., 32, 476 (1967), or by the Lindsey method, as described in "Investigation of a Synthesis of Meso-Porphyrins Employing High Concentration Conditions and an Electron Transport Chain for Aerobic Oxidation," J. Org. Chem., 59, 579-87 (1994). Similar reactions are described for meso-alkyl compounds in "Facile Syntheses of Tetraalkylchlorin and Tetraalkylporphyrin Complexes and Comparison of the Structures of Tetramethylchlorin and Tetramethylporphyrin Complexes of Nickel (II), J. Am. Chem. Soc., 102: 6852-54. (1980) (2) The condensation of dipyrrolic compounds and their counterparts, as described by allace et al., "Rational Tetraphenylporphyrin Syntheses: Tetraarylporphyrins from the MacDonald Route", J. Org. Chem., 58, 7245. -47 (1993). (3) The manipulation of a porphyrin in its ß or meso positions, for example, as described by DiMagno et al., "Facile Elaboration of Porphyrins Via Metal-Mediated Cross-Coupli gs", J. Org. Chem., * 58, 5983-93 (1993); or by Osuka et al., "Synthesis of 5, 15-Diaryl-Substituted Oxochlorins from 5, 15-Diaryl-octaethyl Porphyrin, Bull, Chem. Soc. Japan, 66, 3837-39 (1993); substituents on the appropriately pre-existing meso-substituted phenyl-porphyrins described by Hombrecher et al., "An Efficient Synthesis of Tetraryl Porphyrins Substituted with Ester Groups Bearing Long Alqyl Chains", Tetrahedron, 49:12, 2447-56 (1993). all of the above documents are incorporated herein by reference The compound of the formula (III) used as the starting material for the iodination reaction can be prepared by any of several known synthetic routes. The reaction is as follows: Typically, an equimolar mixture of dipyrromethane and an appropriately substituted aldehyde are reacted under a nitrogen atmosphere with an acid catalysis. The porphyrinogen formed with air or the treatment with DDQ as an oxidant, gives the porphyrin, which is then typically purified by column chromatography.

Preferably, the compound of the formula (II) is prepared using the method described by Manka et al., Tetrahedron Letters, 30 (50), 6989 (1989), which is incorporated herein by reference.

The iodation reaction of the invention is carried out by treating the starting material with an iodinating agent. Any of a large number of iodinating agents can be used, provided that it does not modify or interfere with any of the other substituents present on the compound of the formula (II). Examples of suitable iodinating agents include I2; silver triiodoacetate, tris (triiodoacetoxy) thiol; mixtures of iodine, nitric acid and sulfuric acid; mixtures of iodine and yodic or periodic acid; mixtures of iodine and bis (trifluoroacetoxy) iodobenzene; diacetoxyphenyl iodide; N-iodo-amides, such as N-iodoacet mida, N-iodo-4-nor robenzamide, N-iodo-2,4-dinitrobenzamide and N-iodo-3-succinimide; iodate substrates that are activated toward electrophilic substitution or softly deactivated substrates such as iodobenzenes; mixtures of iodine, potassium permanganate and sulfuric acid; mixtures of iodine-metal such as iodine / silver (I), iodine / copper (II), iodine / lead (IV) or iodine / antimony (V); mixtures of potassium, sodium or an ammonium iodide in trifluoroacetic acid with a metal salt such as cobalt (III), manganese (III) or cerium (IV); combinations thereof; and similar. Preferably, the iodinating agent is selected from the group consisting of bis (trifluoroacetoxy) iodobenzene, I2, N-iodosuccinimide, diacetoxylphenyl iodo, silver triiodoacetate, tris (triiodoacetoxy) thallium, and combinations thereof. A particularly preferred iodation agent is either N-iodosuccinimide or bis (trifluoroacetoxy) iodsbenzene used in combination with iodine. The amount of the iodinating agent is generally stoichiometric, and typically ranges from about 0.75 to about 1.5 equivalents of iodine per mole of the starting tetramacrocyte. Preferably, the amount of the iodinating agent used is about 1.0 equivalent per mole of the starting material. Although the iodation agent can be added to a pure reaction mixture, especially when it is a liquid at room temperature, it is best used dissolved in a suitably non-reactive solvent. When used, the choice of a solvent depends on the configuration of the substituent on the tetramacrocyclic starting material, which affects its solubility. However, the solvents found typically include aromatic solvents, such as pyridine, toluene and benzene; chlorinated solvents, such as CHC13, dichloromethane and 1,1-dichloroethane; water, ethers. such as diethyl ether, tetrahydrofuran, diethylene glycol, and glycol dimethyl ether (ethylene glycol dimethyl ether); ketones such as acetone and pinacolone; acetonitrile; DME, DMF and DMSO; and mixtures thereof. When the starting material is soluble in water, the preferred solvent is water. When an organic solvent is used, particularly useful solvent systems include combinations of chlorinated solvents, such as CHC13, and dichloromethane, mixed with about 2-25% by volume of pyridine. More preferably, the solvent is a mixture of pyridine and chloroform. The temperature of the reaction mixture during iodination can vary widely but is typically maintained at room temperature or somewhat cooled to a temperature in the range of about -10 ° C to room temperature. Preferably, the reaction is carried out at about room temperature. The time required for the iodination reaction of the invention will depend largely on the temperature used and the relative reactivities of the starting materials. Particularly when the meso-substituents are aryl or a bulky alkyl group, such as tert-butyl, the reaction time tends to be relatively slow due to the steric hindrance of the β-positions against the attack of the input iodine radical. Accordingly, even when the di-mesophenyl-substituted systems have been observed to react relatively quickly, the trisubstituted systems, at least where one or more of S1 to S3 are particularly bulky such as a tert-butyl group, a group Cycloalkyl, or a substituted phenyl ring, may require a significantly longer time to complete. Therefore, the reaction time can vary widely, for example, from about 10 minutes to about 7 days. Preferably, the time required for the iodation reaction is in the range of about one to two hours. The iodation reaction can be carried out at pressures both above and below atmospheric pressure. Preferably, however, the reaction is carried out at a pressure approximately equal to atmospheric pressure. The iodization step of the invention can be carried out under ambient, normal lighting conditions. However, because substrates and iodization products are often good photosensitizers, the exclusion of light is sometimes preferred to minimize side reactions. Techniques such as various types of chromatographies, especially thin layer chromatography (CCD) and HPLC, can be used to monitor the progress of the reaction by the disappearance of the starting tetramacrocycle. At the end of the iodation reaction, a reaction mixture is obtained, from which the mono-iodine product can be separated and purified by any conventional means, typically chromatographically. Although the reaction mixture of iodination can be used directly in the methalation, alkynylaion, or other subsequent reaction step without intervening isolation or purification, it is preferable to isolate and / or purify the iodinated compound to minimize the ease of isolation and / or purification of the product so that it falls further down to the synthetic route. In any case, the mono-iodinated compound, for example, H2DPPI (5,15-diphenylporphyrin) can be used as an intermediate to make a wide variety of other compounds. The examples of the useful reagents and the corresponding products for H2DPPI are shown in the table given below:Reagent that is going to react with B2DPPI Expected Product ? / Cu H2DPP-H2DPP Ar-Cu H2DPP-Ar Alq2LiCu H2DPP-Alq R-CaC-Cu H2DPP-C »C-R CF3C02Na / CuI H2DPP-CFj C" F2a., Cu H2DPP-CnF2o., NaCH (C02Et) 2 / CuI H2DPP-CH2-C02H CuCN H2DPP-CN NaCHC C02Et / CuI H2DPP-CH2-CN PhSNa / CuI H2DPP-S-Ph CF3SCu H2DPP-S-CF, CuSCN H2DPP-S-H2DPP ArSeK / CuI H2DPP-Se-Ar KSeCN / CuI H2DPP-Se-CN P- (Ar), / CuI (H2DPP) 4P + r Cl, H2DPP-IC12 XeF2 H2DPP-IF2 [O] H2DPP-IO RC03H H2DPP-I (OCOR) 2 PhH / HX / [O] H2DPP-I-Ph? »/ PhH H2DPP-Ph" Ni "H2DPP-H2HDPP ArMgBr H2DPP-Ar 11 pd II ArZnCl H2DPP-Ar ArCu H2DPP-Ar R-CH = CH2 / "Pd" H2DPP-CH = CH-R Bu4N "Br7" Ni "H2DPP-Br CO / H2 /" Pd "H2DPP-CHO CO / AlqOH / ,, Pd ,, H2DPP-C02Alq O O CO / EtsSn2 / "Pd" ¡|| H2DPP-C-C-H2DPP 0 0 CHr = CH-CII-R H2DPP-CH-CH-CII-R For more information regarding the details of these reactions, see Merkushev, "Advances in the Synthesis of Iodoaromatic Compounds," Synthesis, 923-37 (1988). Where the tetra-locrylic alkyl-substituted sub-compound of (III) is desired, the iodinated product having the formula (I) must be metalated. The metallation step must be carried out between the iodination and the alkynylation binding reaction, since the iodination of the starting tetramacrocycle is facilitated when the metal is not present, and the progress of the alkynylation step is strongly facilitated when a metal is present. In many cases, since a metal ion present increases the solubility of the iodinated intermediate, a higher concentration of the reactants and a shorter reaction time for the alkynylation step becomes possible. Suitable reagents and metallation conditions are widely known to those of ordinary skill in the art. Specifically, any metal salt used in combination with a polar solvent that is capable of metallation is suitable. However, the M in the formula (III) (and therefore the metal in the metal salt) can be any metal species that is capable of forming a metal complex with a compound of the formula (II), and is preferably selected from the group consisting of Ni (II), Cu (II), Zn, Sn, Ge, Si, Ga and Al. Examples of useful metal salts include zinc acetate (II), Ni (II) acetate, Ni (II) ) "ACAC" (acetylacetone), Cu (II) acetate, Cu (II) ACAC, Sn (II) chloride, Sn (IV) chloride, gallium triacetate [Ca (0Ac) _], germanium tetrachloride ( CeCl4), gadolinium triacetate [Ga (0Ac) 3], aluminum trichloride (A1C13), Mn (OAc) 3, silicon tetrachloride (SiCl4) and the like. The use of highly oxidizing metal salts should be avoided because they can adversely affect the stability of the macrocyclic. Preferably, the metal salt is selected from the group consisting of Zn (OAc) 2, Cu (OAc) 2, Ni (OAc.) 2, SnCl 2, SnCl 4 and Gd (0Ac) 3. The above metallation agents are preferably used in combination with a suitable non-reactive solvent Examples of useful solvents include water, alcohols, such as ethanol, methanol, iso-propanol and the like, haloalkanes such as chloroform, methylene chloride, 1,1-dichloroethane and the like; containing nitrogen such as pyridine, dimethylformamide, tetrahydrofuran and the like; relatively non-reactive aromatic compounds such as benzene, toluene and the like, ethers such as diethyl ether, diethylene glycol, and glycol dimethyl ether, and the like. More preferably the solvent organic is methanol, chloroform, pyridine, CH2C12, dichloroethane, or a mixture of any two or three of these solvents.The conditions of metalation must be selected to be c ompatible with the particular substituents present on the tetramacrocyclic compound, iodinated, which is metalated. The temperature of the reaction mixture during the metallation process can vary widely but, typically, it is maintained in the range of about 0 to 120 ° C. For example, refluxing methanol can be used in some circumstances, which provides a temperature of approximately 65 ° C. However, the metallation reaction is more preferably carried out in an approximate manner at room temperature or at a lower temperature. The time required for metallation varies widely, depending on the temperature used and the relative reactivities of the starting materials, particularly the metallation agent. For example, when Zn (OAc) 2 is used as the metallation agent in a mixture of methanol and chloroform as a solvent, the reaction is typically carried out from about 12 to 24 hours, most often in about a period of time. from 16 hours. Preferably, the effective metallation conditions can be very mild. A particularly preferred set of conditions is an excess of 400% Zn (0Ac) 2 in a mixture of 1:10 methanol: chloroform at 80 ° C for 16 hours. The reaction can be carried out above or below atmospheric pressure. Preferably, the reaction is carried out at a pressure approximately equal to atmospheric pressure. The reaction can be carried out in the presence of a gas mixture approaching that of the air but, when particularly reactive gases are involved, the gas mixture can be enriched with an inert gas, such as nitrogen gas, argon, and similar. The direct procedures can be used to isolate the metalated product, such as extraction with any immiscible liquid, elution on a column filled with silica gel or another type of chromatography, submerging in a non-solvent, precipitating it or crystallizing it in another way. r evaporating the solvent, or some combination of these or other conventional methods. Preferred methods of isolation of the desired metallated compound include chromatography and / or crystallization. If further purification of the metallated product is desired, it may be subjected to further purification procedures, elution on a column for chromatography filled with silica gel, and combinations of these methods. Although the reaction mixture for iodination can be used directly in the metallation, alkynylation, or other subsequent reaction step without the intervention of isolation or purification, it is preferable to isolate and / or purify the iodinated compound to minimize the ease of the product for the isolation and / or the purification, so that it falls further down to the synthetic route. Because metallation reactions are known to those with ordinary experience in this technique, additional information can be obtained from J.W. Buchler, "Synthesis and Owners of Metalloporphyrins ", The Porphyrins, Vol. I, Chapter 10 (2978), which is incorporated herein for reference. The metalated product is advantageously linked or coupled with a terminal alkyne to form the corresponding meso-alkynyl tetramacrocycle of the formula (III). Examples of useful alkynes include 3-butin-1-ol, 4-phenyl-1-butyne, 3, 3-diethoxy-1-propynyl, 3-trimethylsilyl-1-yl, long chain alkynes of about 6 to 12 carbon atoms such as 1,7-octadiin and 1-decino, steroids and 3-propynyl sterols, propargyl bromide, propargyl chloride, a propargyl alcohol, a propargyl nitrile, an amine propargyl, propargyl acetate, propargyl tosylate, and the like. Particularly preferred alkyls are of the formula HC = CH wherein R is -C6H5, -CH (OC2H5) 2, Si (CH3) 3, testosterone or estradiol. Typically, the alkynylation process is carried out in the presence of a catalyst such as Pd (PPh3 ^ Cl2 / Cul, Pd (II) OAo, Pd (PPh3) I7 and the like, however, particularly convenient catalysts include Pd ( PPh3) 2Cl2, Cul, and Pd (II) 0Ac More preferably the catalyst is a combination of Pd (PPh3) 2Cl2 and Cul.An organic base usually used in the alkynylation reaction mixture is a scrubber. it is generally one which is a strong but weak nucleophilic base and which, therefore, accelerates the formation of the desired product.Preferred bases include pyridine, imidazole, isoquinoline, ter-alkyl amines such as trimethylamine, triethylamine, methylsulfonamide, and the like. The amount of the base used can vary widely, provided that a sufficient amount is present to neutralize the Hl released during the course of the coupling or coupling reaction, Preferably, however, the amount of the it is used falls within the range of from about 2 to about 20 equivalents. Some bases, such as triethylamine or pyridine, can also be used as solvents or solvents for iodination and / or metallation reactions. Most of the above alkynes are used in combination with a non-reactive organic solvent suitably, such as methanol, ethanol, tetrahydrofuran, DMF, DMSO, and the like, to aid solubilization of the meso-alkenyl product, especially when the product it is an anidonic or cationic species. A particularly preferred combination of the catalyst, base, and solvent for the alkynylation reaction of the invention is Pd (PPh3) 2Cl2 and Cul in a mixture of THF and triethylamine. The temperature of the reaction mixture during the alkynylation reaction can vary widely depending on the catalyst and the solvent system being used. For example, when Pd (PPh3) 2Cl2 is being used as the catalyst, the temperature is typically allowed to remain at about room temperature. When other catalysts are used, however, the temperature may vary from about 1 to about 100 ° C. The time required for the alkynylation reaction of the invention will depend largely on the temperature used and the relative reactivities of the starting materials, but preferably it is about one to twelve hours. The alkynylation reaction can be carried out in the presence of gases at a pressure both above and below the atmospheric pressure. More frequently, however, the reaction is carried out at a pressure approximately equal to atmospheric pressure. The resulting product, a meso-alkynyl tetramacrocycle of the formula (III), can be isolated by any conventional method, such as by immersing it in a non-solvent, removing it by precipitation, extracting it with any immiscible liquid, evaporating it from a solvent, or combination of these or other conventional methods. Typically, the meso-alkynyl compound of the formula (III) can then be purified by one or a combination of known purification techniques, such as recrystallization techniques, various forms of chromatography (e.g. silica / CH2Cl2-0.5% MeOH ), crushing with a non-solvent or partial solvent, vacuum distillation, countercurrent extraction, and the like. A general procedure for joining or coupling the acetylenic derivatives with the meso-mono-monoal tetramaorooyl compounds is as follows: A known amount of a meso-monoiodo tetramacrocycle is dissolved in dry triethylamine or tetrahydrofuran. If the iodide is not sufficiently soluble in triethylamine, an appropriate amount of dimethylformamide or an additional amount of tetrahydrofuran may also be added. Then the bis (triphenylphosphine) palladium (II) chloride, copper (II) iodide, and a 2-3 molar excess of the alkyne to be bound or coupled, are added under a nitrogen atmosphere, stirring either at room temperature environment or with heat when required. The course of the reaction is verified by CCD. The solution is heated or left at room temperature for a time interval of about one to about 48 hours, typically in about two hours. After the reaction is complete, the solvent is removed by evaporation under reduced pressure. The residue is subjected to chromatography, for example, on silica gel.

The meso-alkynyl tetramacrocycle compounds of the invention are useful as photosensitizers used in photodynamic therapy (PDT), as are synthetic intermediates for making or making related photosensitizers. As the photosensitizers, the compounds of the invention are useful in the sensitization of neoplastic cells or other abnormal tissues for destruction by irradiation with visible light. During photoactivation, the photoactivation energy is believed to be transferred to the endogenous oxygen, thus converting it to single oxygen. This simple oxygen is thought by some people to be responsible for the observed cytotoxic effect. Alternatively, direct electron transfer from the photoactivated molecule may exist. The method of van Lier, Photobiological Techniques, 216, 85-98 (Valenzo et al., 1991) can be used to confirm the ability of any given compound to generate simple oxygen effectively, thus making it a good candidate for its use in PDT. In addition, the activated forms of porphyrin are able to fluoresce, and this fluorescence can help to image a tumor. Typical indications known in the art include diagnosis and destruction of tumorigenic tissue in the form of solid tumors, such as those of bronchial, cervical, esophageal or colon cancer; the dissolution of the plates in the blood vessels (see, for example, U.S. Patent No. 4,512,672, which is incorporated herein by reference); the treatment of topical conditions such as acne, athlete's foot, warts, papilloma and psoriasis; and the treatment of biological products, such as blood for transfusion, to eliminate infectious agents. Additionally, when metals such as In or Tc are used, the metallated meso-substituted compounds of the invention have a diagnostic use in nuclear medicine. Similarly, when M is Mn (III) or Gd (III), the compounds may be useful in magnetic resonance imaging. These are also applications where, due to the possible variability with respect to the substitution configurations, significantly improved biodistribution properties can be achieved, using the compounds of the invention. The photosensitizers made from the compounds of the invention can be formulated in pharmaceutical compositions for administration to the patient or applied to a target or in vitro using techniques generally known in the art. A summary of such pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA. The compounds of the invention can be used in single or co or mixtures components. In general, for the diagnosis or treatment of solid tumors, the compound of the invention, labeled or unlabelled, is administered systematically, such as by injection. The injection can be intravenous, subcutaneous, intramuscular, or even intraperitoneal. The injectable substances can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, brine, dextrose, glycerol and the like. Of course, these compositions may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH-buffering agents, and so on. Systematic administration can be implemented through the implantation of a sustained release or slow release system, by a suppository, or, if formulated appropriately, orally. Formulations for these modes of administration are well known in the art, and a summary of such methods can be found, for example, in Remington's Pharmaceutical Sciences (supra). If the treatment is to be located, such as for the treatment of superficial tumors or skin disorders, the compound may be administered topically using standard topical compositions, such as lotions, suspensions, or pastes. The amount of the photosensitizing compound to be administered depends on the choice of the active ingredient, the condition to be treated, the mode of administration, the individual subject or patient, and the judgment of the physician. Depending on the specificity of the preparation, smaller or larger doses may be necessary. For compositions that are highly specific for target or target tissues, such as those with a highly specific monoclonal immunoglobulin preparation or a specific receptor ligand, dosages in the range of 0.05-1 mg / kg are suggested. For compositions that are less specific with respect to target or target tissue, larger doses, up to 1-10 mg / kg, may be necessary. The preceding intervals are merely suggestive, because the number of variables with respect to an individual treatment regimen is large, and considerable excursions from these recommended values are common. In addition to in vivo use, the compounds made from the intermediate iodinated compounds of the invention can be used in the treatment of in vitro materials to destroy harmful viruses or other infectious agents. For example, blood plasma or blood to be used for transfusion or to be put in a bank for future transfusion can be treated with the compounds of the invention and irradiated to effect sterilization. In addition, biological products such as Factor VIII, which are prepared from biological fluids, can be irradiated in the presence of the compounds of the invention to destroy contaminants. Synthetic routes of potential interest which may be sought with the meso-alkynyl tetramacrocycle of the invention include the formation of the meso-ethynyl diphenyl porphyrins, followed by a second coupling or coupling reaction to another iodinated compound. The introduction of the meso-alkynyl group usually gives the molecule an amphiphilic character, a property that may be important in the biodistribution of site-specific photochemotherapeutic characteristics. In addition, because the groups S1 to S3 in the three meso positions can be the same or different, and can be substituted by themselves either symmetrically or asymmetrically, the compounds of the invention can be "tuned in fine form" to produce a desired set of biological effects when administered to a subject in need of PDT. Still further, the invention provides methods for synthesizing these compounds in an efficient manner with relatively few isomeric byproducts or impurities. If desired, the product can be subjected to a simple general demetalation procedure as follows: The metalated version of the desired meso-alkylated compound is dissolved in methylene chloride, and a small amount of trifluoroacetic is added. The resulting green solution is stirred for five minutes and poured into water. The organic phase is separated, washed with water, and dried over an anhydrous desiccant. Filtration of the organic phase and evaporation of the solvent provide the corresponding metal free tetramacrocycle, usually in quantitative yields. The invention will be further clarified by the following examples, which are proposed to be illustrative only of the invention.

Example 1: Iodination of 5, 15-Diphenylporphyrin 50 mg (0.11 mmol) of the 5, 15-diphenyl porphyrin are dissolved in 50 ml of CHC13. 3 ml of an iodine solution in chloroform (0.055) is added to the stirred solution.

M) Finally, a solution of 50 mg (0.12 mmoles) of bis (trifluoroacetoxy) iodobenzene dissolved in 25 ml of chloroform is added dropwise, followed by 200 μl of pyridine. The mixture is stirred at 25 ° C, in the dark, for one hour. After evaporation of the solvent in vacuo, the residue is subjected to chromatography on silica gel, eluting with 50% of 1,1-dichloromethane in hexane to give 44 mg of the 10-iodo-5,15-diphenylporphyrin. (70% yield). UV-Vis (CH2C12):? ^ 422, 520, 560, 600, 660 nm; MS (El) m / e 588 (100).

The wavelengths for the electronic absorption spectrum are shown in Figure 1: Absorbance wavelength 422 1.122314 518 0.086899 558 0.069290 580 0.053253 606 0.050903 Example 2: Metalation of 10-iodo-5, 15-diphenylporphyrin 50 mg (85 μmoles) of the iodinated starting compound, 10-iodo-5,15-diphenylporphyrin are dissolved in 30 ml of CHC13, and the stirred solution is brought to reflux under an N2 atmosphere. A solution of 100 mg (0.456 mmol) of Zn (OAc) 2H2? in 5 ml of methanol was added, and the mixture is refluxed for 16 hours. Following evaporation of the solvent in vacuo, the residue is passed through a short column of neutral alumina, eluting with methylene chloride. Evaporation of the solvent gave 48 mg of 10-iodo-5,15-diphenylporphyrin zinc (87% yield). 1 H NMR (400 MHz, Pyridine d5) d = 7.74-7.78 (m, 6H); 8.3 (dd, J = 6.22, 1.13Hz, 4H); 9.11 (dd, 4.72, < lHz, 4H); 9.48 (d, 4.46Hz, 2H); 10.03 (d, 4.61Hz, 2H); 10.36 (s, 1H). UV-Vis (CH2C12):? ^ 420, 548 nm; EM (H) m / e cale - for C32HI9N4IZn (M +): 649.9946, found: 649.9936.

The annotated wavelengths for the electronic absorption spectrum shown in Figure 2: Wavelength Absorbency 420 2.127029 548 0.160812 Example 3: Alkylation of 10-iodo-5, 15-diphenylporphyrin Zinc The product compound of Example 2, 10-iodo-5,15-diphenyl-orphyrin zinc (10 mg, 15.4 μmol) is dissolved in 10 ml of dry tetrahydrofuran. Bis (triphenylphosphine) -paladis (SI) chloride (2 mg, 2.8 μl.), Copper (I) iodide (10 mg, 53 μmol), and triethylamine (100 μmol) are added to the stirred solution. 34 μmoles of the alkyne, HC = C- (CH2) 2-C ?, were added, and the mixture was stirred at 25 ° C for two hours.The solvent was completely evaporated in vacuo, and the residue was subjected to chromatography on silica gel to give the 10-alkynylated-5, 15-diphenylporphyrin zinc (89% yield).

NMR (400 MHz, CDCl 3) 6 = 2.91 (t, J-ß.lHz, 2H); 3.75-3.79 (m, 2H); 7.73-7.78 (m, 6H); 8.19 (dd, J = 6.24, 1.37Hz, 4H); 8.95 '(dd, J = 4.74, < lHz, 4H); 9.24 (d, J-4.45HZ, 2H); 9.55 (d, J = 4.54Hz, 2H); 10.07 (s, 1H); UV-Vis (CH2Cl2):? - ^ = 422, 552, 590 nm; MS m / e cale, for C36H24N4OZn (M +): 592.1241, found: 592.1236.

The lengths noted for the electron absorption spectrum shown in Figure 3: Wavelength Absorbency 584 0.066940 552 0.149658 422 2.051956 Example 4: Preparation of Other Meso-alkynyl Tetramacrocycles R = CH (OC2H5) 2 R = Si (CH3) 3 The above five compounds were prepared according to the general alkynylation procedure described in Example 3 above. The following data was obtained for each product: Yield = 85%; X H NMR (400 MHz, CDC13) d-7.54-7.57 (m, 3H); 7.74-7.81 (, 6H); 8. 02 (dd, J-7.31, < 1HZ, 2H); 8.21 (dd, J = 7.61, 2Hz, 4H); 8.98 (d, J = 4.46Hz, 2H); 9.01 (d, J = 4.51Hz, 2H); 9.3 (d, J = 4.51Hz, 2H); 9.84 (d, J = 4.68, 2Hz); 10.15 (s, 1H); UV-Vis (CH2C12)? - ^ 432, 558, 600, 634 nm; MS m / e cale, for C40H24N4Zn (M +): 624.1292, found: 624.1285.

Annotated wavelengths for the electronic absorption spectrum shown in Figure 4: Wavelength Absorbency 408 0.343811 432 1.077454 446 0.408539 558 0.088120 600 0.080658 634 0.070648 • R = CH (OC2H5) 2: Yield = 61%; 1N NMR (400 MHz, CDCl 3) d-1.19 (t, J = 7.07 Hz, 6H); 3.52-3.59 (, 2H); 3.65-3.72 (m, 2H); 5.25 (s, 1H); 7.73-7.77 (m, 6H); 8.19 (dd, J = 5.64, 1.37Hz, 4H); 8.99 (dd, J »5.01, < lHz, 4H); 9. 32 (d, J-4.59HZ, 2H); 9.72 (d, J-4.56HZ, 2H); 10.19 (s, 1H); UV-Vis (CH2C12)? - "= 422, 552, 584 nm; EM m / e cale, for C39Hj0M «O2Zn (M +): 650.1660, encont .: 650.1658.

The annotated wavelengths for the electronic absorption spectrum shown in Figure 5: Wavelength Absorbency 584 0.064743 552 0.128479 422 1.900803 R = Si (CH3) 3 Yield = 71%; H-NMR (400 MHz, CDCl 3) d = 0.59 (s, 9H); 7.73-7.79 (m, 6H); 8.2 (dd, J = 5.76, 1.49Hz, 4H); 8.99 (dd, J = 4.55, < lHz; 4H); 9.31 (d, J = 4.46Hz, 2H); 9.77 (d, J = 4.69Hz, 2H); 10.17 (s, 1H); UV-Vis (CH2C12)? - ^ = 424, 556 nm; MS m / e cale, for C37H2gN4SiZn (M +): 620.1375, found: 620.1370.

Annotated wavelengths for the electronic absorption spectrum shown in Figure 6: Wavelength Absorbency 424 1.039230 556 0.084732 510 0.055023 R = testosterone Yield = 60%; 1R NMR (400 MHz, CDCl 3) d = 1.14 (s, 3H); 1.21 (s, 3H); 2.9-3 (m, 2H); 5.56 (s, 1H); 7.73-7.78 (m, 6H); 8.18 (dd, J = 6, 1.56Hz, 4H); 8.98 (d, J = 4.44Hz, 2H); 9.01 (d, J = 4.45Hz, 2H); 9.29 (d, J = 4.44Hz, 2H); 9.68 (d, J = 4.67Hz, 2H); 10.15 (3, 1H); UV-Vis (CH2C12)? - ^ = 424, 554, 592 nm; EM m / e cale, for C ^ H ^ O.Zn (M +): 834.2912, encont .: 834.2903. The annotated wavelengths for the electronic absorption spectrum shown in Figure 7: Wavelength Absorbency 424 2.401733 554 0.206039 592 0.097625 R = estradiol Yield = 53%; H-NMR (400 MHz, CDCl 3) d = 1.14 (s, 3H); 2.7-3.05 (m, 4H); 4.49 (samp., 1H); 6.52 (d, J = 2.34Hz, 1H); 6.57 (dd, J-8.39, 2.34Hz, 1H); 7.16 (d, J = 8.41Hz, 1H); 7.75-7.79 (m, 6H); 8.91 (dd, J = 7.63, 1.77Hz, 4H); 9.0 (d, J = 4.66Hz, 2H); 9.02 (d, J = 4.66Hz, 2H); 9.31 (d, J = 4.52Hz, 2H); 9.76 (d, J = 4.71Hz, 2H); 10.17 (s, 1H); UV-Vis (CH2C12)? ™ = 424, 554, 592 nm; EM m / e cale, for CjjH ^ C ^ Zn (M +): 834.2912, encont .: 834.2903.

Annotated wavelengths for the electronic absorption spectrum shown in Figure 8: Wavelength Absorbency 424 1.509140 554 0.415894 Example 5: Alkynylation with HCBC- (CHg ^ CaCH mg of the meso-iodized product, starting metalate, from Example 3 above are dissolved in 10 ml of dry tetrahydrofuran. The bis (triphenylphosphine) palladium (II) chloride (2 mg, 2.8 μmol), copper (I) iodide (10 mg, 53 μmol), and 100 μl of triethylamine are added to the stirred solution. Finally, 1, 7-octadiin (50 μl, 0.377 mmol) is added, and the mixture is stirred at 25 ° C for two hours. The solvent was removed by evaporation in vacuo, and the residue was chromatographed on silica gel to give 10- (1,7-octadiinyl) -5, 15-diphenylporphyrin zinc. The yield was 55%.

X H NMR (400 MHz, CDC13): d = 2-2.12 (m, 5H); 2.94 (t, J = 6.77Hz, 2H); 3.06 (t, J = 6.77Hz, 2H); 7.73-7.79 (m, 6H); 8.21 (dd, J = 5.66, 1.9Hz, 4H); 8.99 (dd, J = 4.43, < lHz, 4H); 9.31 (d, J = 4.51Hz, 2H); 9.75 (d, J = 4.48Hz, 2H); 10.16 (s, 1H); UV-Vis (CH2C12):? ^. - 422, 548, 582 nm; EM m / e cale, for C ^^ Zn (M +): 628.1605, encont .: 628.1601.

Wavelengths annotated for the electronic absorption spectrum shown in Figure 9: Wavelength Absorbency 720 0.058578 656 0.075485 582 0.081009 548 0.081055 Example 6: Demetallation of Alkylated Product μmol of starting material, 10- (3-hydroxy-1-butynyl) -5,15-diphenylporphyrin zinc are dissolved in 10 ml of CH 2 C 12, and 50 μl of trifluoroacetic acid are added. The resulting green solution is stirred for five minutes. The mixture is poured into 100 ml of water. The organic phase was separated, washed with water (3 X 100 ml), and dried over anhydrous potassium carbonate. The organic phase is filtered and evaporated to dryness to give the free 10- (3-hydroxy-l-butynyl) -5, 15-diphenyl porphyrin of the corresponding metal with a quantitative yield.

It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention is that which is clear from the present description of the invention.

Having described the invention as above, ma as property contained in the following

Claims (24)

1. CLAIMS 1. A meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): characterized in that: each of A to D is independently a ring containing nitrogen, of 5 elements, having the necessary elements to complete a porphyrin, chlorine, bacteriochlorin or isobacteriochlorin nucleus; Ri to R3 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or an acid ester group, keto, hydroxy, nitro, amino, or a group which, taken together with another ring, ring substituent or meso-substituent, forms a ring of 5 or 6 elements fused; and each of S1 to S3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heterocyclic ring.
2. 2. The compound according to claim 1, characterized in that A to D and Ri to R8 have the necessary elements to make or manufacture a core of porphyrin, chlorine, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin.
3. 3. The compound according to claim 1, characterized in that Ri to R8 are independently hydrogen, methyl, ethyl, or lower alkyl esters.
4. 4. The compound according to claim 1, characterized in that S1 to S3 are selected from the group consisting of phenyl, naphthyl, pyridinyl, salts of N-lower alkyl pyridinium, indolyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl , indolizinyl, furanyl, and thiophenyl.
5. 5. The compound according to claim 1, characterized in that at least one of S1 to S3 has the structure: wherein X, X ', Y, Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid or acid salt, sulfonic acid ester, acid phosphonic, phosphate, phosphate ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z 'is hydrogen or lower alkyl.
6. 6. The compound according to claim 5, characterized in that X, X ', Y, Y' and Z are selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, methoxy, hydroxy, OR where R is a group alkyl or a fatty acid group having from 6 to 18 carbon atoms, fluoro, chloro, iodo, bromo, -C (0) -0CH3, cyano, nitro, or a specific ligand for a biological receptor.
7. 7. The compound according to claim 5, characterized in that X, X ', Y and Y' are each hydrogen, and Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or salt acid, carboxylic acid ester, 3-sulphonic acid ester, sulfonic acid or acid salt, phosphonic acid, phosphate, phosphate ester, nitro, amino, cyano, and a biologically active group.
8. 8. The compound according to claim 5, characterized in that at least one of X, X ', Y, Y' and Z is a biologically active group or a substituent that increases the amphiphilic nature of the molecule.
9. 9. The compound according to claim 1, characterized in that each of S1 to S3 is selected from the group consisting of phenyl, pyridinyl, salts of N-lower alkyl pyridinium, indolyl, pyrazinyl, pyridinyl, i-idazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, indolizinyl, furanyl, and thiophenyl.
10. 10. The compound according to claim 9, characterized in that at least two of S1 to S3 are identical.
11. 11. A method for synthesizing a meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): c or wherein each of A to D is independently a ring containing nitrogen, of 5 elements, which has the necessary elements to complete a nucleus of porphyrin, chlorine, bacteriochlorin or isobacteriochlorin; Ri to Re are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or an ester group of the acid, keto, hydroxy, nitro, amino, or a group which, taken together with another ring, substituent of ring or meso-substituent, forms a ring of 5 or 6 elements, fused; and S1 to S3 are H, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings, or substituted or unsubstituted heterocyclic rings, which may be the same or different, characterized in that it comprises the step of treating a porphyrin having the formula (II): with an iodinating agent to form the tetramacrocyclic compound of the formula (I).
12. 12. The method according to claim 11, characterized in that at least one of A to D and Ri to Rs have the necessary elements to make or manufacture a core of porphyrin, chlorine, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin.
13. 13. The method according to claim 11, characterized in that Ri to R8 are independently hydrogen, methyl, ethyl, or lower alkyl esters.
14. 14. The method according to claim 11, characterized in that at least one of S1 to S3 has the structure: wherein X, X ', Y, Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid or acid salt, sulfonic acid ester, acid phosphonic, phosphate, phosphate ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z 'is a hydrogen or lower alkyl.
15. 15. The method according to claim 14, characterized in that at least one of X, X ', Y, Y' and Z is a biologically active group or a group that increases the amphiphilic nature of the molecule.
16. 16. The method according to claim 11, characterized in that the iodinating agent is selected from the group consisting of bis (trifluoroacetoxy) iodobenzene, I2, N-iodosuccinimide, diacetoxyphenyl iodo, silver triiodoacetate, tris (triiodoacetoxy) thallium, and combinations of the same.
17. 17. The method according to claim 11, characterized in that the treatment step is carried out in an organic solvent which is selected from the group consisting of chloroform, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, asetonitrile and diethyl ether.
18. 18. The method according to claim 11, characterized in that the step of the treatment is carried out in the dark.
19. 19. The method according to claim 11, characterized in that the treatment step is carried out at room temperature.
20. 20. The method according to claim 11, characterized in that the treatment step is carried out in less than two hours. 21. A method for synthesizing a meso-alkynyl tetramacrocyclic compound having the formula (III): wherein M is a metal selected from the group consisting of Ni (II), Cu (II), Zn, Sn, Ge, Si, Ga, Al, Mn (III), Gd (III), In and Tc; each of A to d is independently a ring containing nitrogen, of 5 elements having the necessary elements to complete a nucleus of porphyrin, chlorine, bacteriochlorin or isobacteriochlorin; R1 to R1 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or an ester group of the acid, keto, hydroxy, nitro, amino, or a group which, taken together with another ring, substituent of ring or meso-substituent, forms a ring of 5 or 6 elements, fused; S1 to S3 are H, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted aromatic rings, or substituted or unsubstituted heterocyclic rings, which may be the same or different; and R9 is an organometallic radical, a substituted or unsubstituted alkyl group having from 1 to 30 carbon atoms, aromatic, heterocyclic, or a biological substrate; characterized in that it comprises the steps of: a. treating a tetramacrocyclic compound having the formula (II): s 1 C i I D with an iodination agent to form the corresponding meso-monoiodo-substituted compound of the formula (I): b. metalating the meso-monoiodo-substituted compound to form the corresponding metalated compound; and c. alkylating the metallated compound in the presence of an alkyne having the formula HCdCH-R9 to give the meso-alkynyl tetramacrocyclic compound of the formula (III).
21. 21. The method according to claim 20, characterized in that at least one of A to D and Ri to R8 have the necessary elements to form a core of porphyrin, chlorine, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin.
22. 22. The method according to claim 20, characterized in that M is Zn.
23. 23. The method according to claim 20, characterized in that at least one of A to D and Ri to R »has the necessary elements to make or manufacture a core of porphyrin, chlorine, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin.
24. 24. The method according to claim 20, characterized in that Rx to R8 are independently hydrogen, methyl, ethyl, or lower alkyl esters. 26. The method according to claim 20, characterized in that Rg is selected from the group consisting of SiMe3, substituted or unsubstituted phenyl, pyridyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrrolyl, thiophenyl, furanyl, and biological substrates. 27. The method according to claim 20, characterized in that at least one of S1 to S3 has the structure: wherein X, X ', Y, Y' and Z are independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, carboxylic acid or acid salt, carboxylic acid ester, sulfonic acid or acid salt, sulfonic acid ester, acid phosphonic, phosphate, phosphate ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z 'is hydrogen or lower alkyl. 27. The method according to claim 25, characterized in that at least one of X, X ', Y, Y' and Z is a biologically active group or a group that increases the amphiphilic nature of the molecule. 28. The method according to claim 20, characterized in that the iodinating agent is selected from the group consisting of bis (trifluoroacetoxy) iodobenzene, I2, N-iodosuccinimide, diacetoxyphenyl iodo, silver triiodoacetate, tris (triiodoacetoxy) thallium, and combinations of the same. 29. A method according to claim 28, characterized in that the processing step a. it comprises treating the compound of the formula (II) with a bis (trifluoroacetoxy) iodobenzene in the presence of I2. 30. The method according to claim 20, characterized in that the processing step a. It is carried out at room temperature and in the dark. 31. The method according to claim 20, characterized in that the metallation step b. comprises treating the meso-monoiodo-substituted compound with a metallating agent selected from the group consisting of Zn (OAc) 2H20, Ga (0Ac) 2, Cu (0Ac) 2, Ni (0Ac) 2r GeCl 4, Gd (0Ac) 3 , A1C13, SnCl, Mn (0Ac) 2, SIC14. 32. The method according to claim 20, characterized in that, in the alkynylation step c, the corresponding metallated compound is treated with said alkyne in the presence of a catalyst. 33. The method according to claim 32, characterized in that the catalyst is bis (triphenylphosphine) palladium (II) chloride / copper (I) iodide. SUMMARY DB THE INVENTION The present invention relates to a meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): c n wherein: each of A to D is independently a ring containing 5-element nitrogen, which has the necessary elements to complete a core of porphyrin, chlorine, bacteriochlorin or isobacteriochlorin; Ri to R8 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or an ester group of the acid, keto, hydroxy, nitro, amino, or a group which, taken together with another ring, substituent of ring or meso-substituent, forms a ring of 5 or six elements, fused; and each of S1 to S3 is H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heterocyclic ring. A method for synthesizing the compound comprises the step of iodinating a corresponding, non-halogenated, dismetalated tetramacrocyclic compound followed by the metalation. The compound of the invention is an intermediate capable of binding or coupling with an alkyne to achieve or obtain a desired mono-mesoalkynyl compound.