# US 5,703,230 A · Meso-monoiodo-substituted tetramacrocyclic compounds and methods for making and using the same > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,703,230 A - Document ID: US5703230A - Status: Granted - Kind: A - Application number: 08/349,179 - Filed: 1994-12-02 - Granted: 1997-12-30 - Earliest claimed: 1994-12-02 - Assignees: The University of British Columbia - Inventors: Ross W. Boyle; David Dolphin; Claire K. Johnson - Web page: https://patentgrep.com/patent/US5703230A ## CPC - C07D 487/22: in which the condensed system contains four or more hetero rings - A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors - A61P 17/00: Drugs for dermatological disorders - A61P 31/04: Antibacterial agents - A61P 35/00: Antineoplastic agents - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract A meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): ##STR1## wherein: each of A through D is independently a 5-membered, nitrogen-containing ring having the members necessary to complete a porphyrin, chlorin, bacteriochlorin or isobacteriochlorin nucleus; R.sub.1 through R.sub.8 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino, or a group that, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membered ring; and each of S.sup.1 through S.sup.3 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 unhalogenated, de-metallated tetramacrocyclic compound, followed by metallating. The compound of the invention is an intermediate capable of coupling with an alkyne to achieve a desired mono-meso-alkynyl compound. ## Claims ### Claim 1 A meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): ##STR20## wherein: each of A tough D is independently a 5-membered, nitrogen-containg ring having the members necessary to complete a porphyrin, chlorin, bacteriochlorin or isobacteriochlorin nucleus; R.sub.1 through are R.sub.8 independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino, or R.sub.1 and R.sub.2, R.sub.3 and R.sub.4, R.sub.5 and R.sub.6, or R.sub.7 and R.sub.8, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membored ring selected from the group consisting of cyclopentane, furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole pyrazole, 2-isoimidole, 1,2,3-triazole, 1,2,4-triazole, 1,2-dithiole, 1,3-dithiole, 1,2,3-oxathiole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiathiazole, 1,2,4-oxdiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1,2,5-oxathiazole, 1,3-oxathiole, 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, 1,2,6-oxathiazine, 1,3,5,2-oxaciazine, morpholine, azepine, oxepin, thiepin and 1,2,4-diazepine; and each of S.sup.1 through S.sup.3 is H, substituted or unsubstituted alkyl having about 1 to about 18 carbon atoms, and wherein said alkyl group is substituted by a group selected from the group consisting of a halogen atom, a hydroxy group, thiol, a carbonyl group, a primary amino group, a secondary amino group, a tertiary amino group, a quaternary amino group, nitrile, a phosphate group and a sulfonate group, substituted or unsubstituted cycloalkyl having about 3 to about 7 carbon atoms, and wherein said cycloalkyl group is substituted by a group selected from the group consisting of halogen atom, a hydroxy group, thiol, a carbonyl group, a primary amino group, a secondary amino group, a tertiary amino group, a quaternary amino group, nitrile, a phosphate group and a sulfonate group, a substituted or unsubstituted aromatic ring having about 5 to about 12 carbon atoms, or a substituted or unsubstituted heterocyclic ring selected from the group consisting of furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, 1,2-dithiole, 1,3-dithiole, 1,2,3-oxathiazole, isoxazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxathiazole, 1,3-oxathiazole, benzene, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl pyridinium, pyrdazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2,4-oxazlne, 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, 1,3,5,2-oxadiazine, azepine, oxepin, thiepin, 1,2,4-diazepine, indene, isoindene, benzofuran, isobenzofuran, thionaphthene, isothionaphthene, indole, indolenine, 2-isobenzazole, 1,4-pyrindine, pyrando›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-benzodiine, 1,3-benzodiazine, naphthyridine, pyrido›3,4-b!-pyridine, pyrido›3,2-b!-pyridine, pyrido›4,3-b!-pyridine, 1,3,2-benzoxazine, 1,4,2-benzoxazine, 2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, anthracene, phenanthrene, carbazole, xanthene, acridine and purine. ### Claim 2 (depends on 1) The compound of claim 1 wherein A through D and R.sub.1 through R.sub.8 have the members necessary to make a porphyrin, chlorin, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin nucleus. ### Claim 3 (depends on 1) The compound of claim 1 wherein R.sub.1 through R.sub.8 are independently hydrogen, methyl, ethyl, or lower alkyl esters. ### Claim 4 (depends on 1) The compound of claim 1 wherein S.sup.1 through S.sup.3 are selected from the group consisting of phenyl, naphthyl, pyridinyl, lower N-alkyl pyridinium salts, indolyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, indolizinyl, furanyl, and thiophenyl. ### Claim 5 (depends on 1) The compound of claim 1 wherein at least one of S.sup. through S.sup.3 has the structure: ##STR21## 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, phosphonic acid, phosphato, phosphate ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group selected from sugar derivatives, amino acid derivatives, peptides and nucleosides derivatives, and Z' is hydrogen or lower alkyl. ### Claim 6 (depends on 5) The compound of claim 5 wherein X, X', Y, Y' and Z are selected from the group consisting of hydrogen, methyl, ethyl, t-butyl, methoxy, hydroxy, OR where R is an alkyl group or a fatty acid group having from 6 to 18 carbon atoms, fluoro, chloro, iodo, bromo, --C(O)--OCH.sub.3, cyano, nitro, or a ligand specific for a biological receptor. ### Claim 7 (depends on 5) The compound of claim 5 wherein 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 acid salt, carboxylic acid ester, sulfonic acid ester, sulfonic acid or acid salt, phosphonic acid, phosphato, phosphate ester, nitro, amino, cyano, and a biologically active group. ### Claim 8 (depends on 5) The compound of claim 5 wherein 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. ### Claim 9 (depends on 1) The compound of claim 1 wherein each of S.sup.1 through S.sup.3 is selected from the group consisting of phenyl, pyridinyl, lower N-alkyl pyridinium salts, indolyl, pyrazinyl, pyrimidinyl, imidazolyl, triazolyl, pyrrolyl, pyrazolyl, pyridazinyl, indolizinyl, furanyl, and thiophenyl. ### Claim 10 (depends on 9) The compound of claim 9 wherein at least two of S.sup.1 through S.sup.3 are identical. ### Claim 11 A method for synthesizing a meso-monoiodo-substituted tetramacrocyclic compound having the formula (I): ##STR22## wherein each of A through D is independently a 5-membered, nitrogen-containing ring having the members necessary to complete a porphyrin, chlorin, bacteriochlorin or isobacteriochlorin nucleus; R.sub.1 through R.sub.6 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino, or a group that, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membered ring; and S.sup.l throuh S.sup.3 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, comprising the step of treating a porphyrin having the formula (II): ##STR23## with an iodinating agent to form the tetramacrocyclic compound of formula (I). ### Claim 12 (depends on 11) The method of claim 11 wherein at least one of A through D and R.sub.1 through R.sub.8 have the members necessary to make a porphyrin, chlorin, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin nucleus. ### Claim 13 (depends on 11) The method of claim 11 wherein R.sub.1 through R.sub.8 are independently hydrogen, methyl, ethyl, or lower alkyl esters. ### Claim 14 (depends on 11) The method of claim 11 wherein at least one of S.sup. through S.sup.3 has the structure: ##STR24## 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, phosphonic acid, phosphato, phosphate ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z' is hydrogen or lower alkyl. ### Claim 15 (depends on 14) The method of claim 14 wherein 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. ### Claim 16 (depends on 11) The method of claim 11 wherein said iodinating agent is selected from the group consisting of bis(trifluoroacetoxy) iodobenzene, I.sub.2, N-iodosuccinimide, diacetoxyphenyl iodine, silver triiodoacetate, tris(triiodoacetoxy) thallium, and combinations thereof. ### Claim 17 (depends on 11) The method of claim 11 wherein said treating step takes place in an organic solvent is selected from the group consisting of chloroform, pyridine, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile and diethyl ether. ### Claim 18 (depends on 11) The method of claim 11 wherein said treating step is carried out in darkness. ### Claim 19 (depends on 11) The method of claim 11 wherein said treating step takes place at room temperature. ### Claim 20 (depends on 11) The method of claim 11 wherein said treating step takes place in less than two hours. ### Claim 21 A method for synthesizing a meso-alkynyl tetramacrocyclic compound having the formula (III): ##STR25## 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 through D is independently a 5-membered, nitrogen-containing ring having the members necessary to complete a porphyrin, chlorin, bacteriochlorin or isobacteriochlorin nucleus; R.sub.1 through R.sub.8 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino, or a group that, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membered ring; S.sup.1 through S.sup.3 are H, substituted or unsubstituted alkyl groups, substituted or unsubstituted cycloalkyl groups, or substituted or unsubstituted aromatic rings, or substituted or unsubstituted heterocyclic rings, which may be the same or different; and R.sub.9 is an organometallic radical, a substituted or unsubstituted alkyl group having from 1 to 30 carbon atoms, aromatic, heterocyclic, or a biological substrate; comprising the steps of: a. treating a tetramacrocyclic compound having the formula (II): ##STR26## with an iodinating agent to form the corresponding meso-monoiodo-substituted compound of formula (I): ##STR27## b. metallating said meso-monoiodo-substituted compound to form the corresponding metallated compound; and b. alkynylating said metallated compound in the presence of an alkyne having the formula HC.tbd.CH--R.sub.9 to give the meso-alkynyl tetramacrocyclic compound of formula (III). ### Claim 22 (depends on 20) The method of claim 20 wherein at least one of A through D and R.sub.1 through R.sub.8 have the members necessary to make a porphyrin, chlorin, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin nucleus. ### Claim 23 (depends on 20) The method of claim 20 wherein M is Zn. ### Claim 24 (depends on 20) The method of claim 20 wherein at least one of A through D and R.sub.1 through R.sub.8 have the members necessary to make a porphyrin, chlorin, bacteriochlorin, benzochlorin, hydroxychlorin or hydroxybacteriochlorin nucleus. ### Claim 25 (depends on 20) The method of claim 20 wherein R.sub.1 through R.sub.8 are independently hydrogen, methyl, ethyl, or lower alkyl esters. ### Claim 26 (depends on 20) The method of claim 20 wherein R.sub.9 is selected from the group consisting of SiMe.sub.3, substituted or unsubstituted phenyl, pyridyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrrolyl, thiophenyl, furanyl, and biological substrates. ### Claim 27 (depends on 20) The method of claim 20 wherein at least one of S.sup.1 through S.sup.3 has the structure: ##STR28## 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, phosphonic acid, phosphato, phosphate ester, substituted or unsubstituted amino, cyano, nitro, or a biologically active group, and Z' is hydrogen or lower alkyl. ### Claim 28 (depends on 25) The method of claim 25 wherein 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. ### Claim 29 (depends on 20) The method of claim 20 wherein said iodinating agent is selected from the group consisting of bis(trifluoro-acetoxy) iodobenzene, I.sub.2, N-iodosuccinimide, diacetoxyphenyl iodine, silver triiodoacetate, tris(triiodoacetoxy) thallium, and combinations thereof. ### Claim 30 (depends on 29) The method of claim 29 wherein said treating step a. comprises treating the compound of formula (II) with bis(trifluoroacetoxy)iodobenzene in the presence of I.sub.2. ### Claim 31 (depends on 20) The method of claim 20 wherein said treating step a. takes place at room temperature and in the dark. ### Claim 32 (depends on 20) The method of claim 20 wherein said metallating step b. comprises treating said meso-monoiodo-substituted compound with a metallating agent selected from the group consisting of Zn(OAc).sub.2 .multidot.H.sub.2 O, Ga(OAc).sub.3, Cu(OAc).sub.2, Ni(OAc).sub.2, GeCl.sub.4, Gd(OAc).sub.3, AlCl.sub.3, SnCl.sub.2, SnCl.sub.4, Mn(OAc).sub.2, SiCl.sub.4. ### Claim 33 (depends on 20) The method of claim 20 wherein, in said alkynylating step c., said corresponding metallated compound is treated of said alkyne in the presence of a catalyst. ### Claim 34 (depends on 33) The method of claim 33 wherein said catalyst is bis(triphenylphosphine)palladium(II) chloride/copper(I) iodide.