LU101031B1 - Specifically glyco-substituted porphyrins and chlorins for photodynamic therapy - Google Patents

Abstract

The present invention provides certain tetrapyrrolic compounds having a structure of Formula 1, 2, or 3: H or O-R is a substituent in the mefa or para position of the phenyl ring, R1 is a glyco-substituent derived from a mono-, di-, or trisaccharide group, and each R2 is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, phenyl, pentafluorophenyl, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-p-D-glucosyl)-2,3,5,6-tetrafluorophenyl, 4-(1'-thio-p- D-galactosyl)-2,3,5,6-tetrafluorophenyl, mefa- or para-hydroxyphenyl, mefa- or para-carboxyphenyl, and mefa- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH2CH2O)nCH3 with n = 1-30.

Description

P 106691 10.12.2018 LU101031 Description SPECIFICALLY GLYCO-SUBSTITUTED PORPHYRINS AND CHLORINS FOR PHOTODYNAMIC

THERAPY Field of the Invention The invention relates generally to photodynamic therapy, more particularly to specifically glyco-substituted porphyrins and chlorins to be used as photosensitizers for the treatment of hyperproliferative diseases, especially cancer. Background of the Invention Photodynamic therapy (PDT) is one of the most promising techniques being explored for use in a variety of medical applications (Photodynamic therapy, basic principles and clinical applications. Eds. B. W. Henderson, Th. J. Dougherty, Marcel Dekker, 1992, New York; A. P. Castano et al., Photodiagn. Photodyn. Ther. 2004, 1, 279-293; A. P. Castano et al., Photodiagn. Photodyn. Ther. 2005, 2, 1-23; R. R. Allison, C. H. Sibata, Photodiagn. Photodyn. Ther. 2010, 7, 61-75), and, particularly, is a well-recognized treatment for the destruction of tumors (Photodynamic tumor therapy. 2" and 3" generation photosensitizers. Ed. J. G. Moser, Harwood Academic Publishers, 1998, Amsterdam). Photodynamic therapy uses light and a photosensitizer (a dye) to achieve its desired medical effect. In principle, after light activation the triplet state of the photosensitizer is formed which interacts with neighboring molecules among them oxygen which is present in alt cells. By this, reactive oxygen species, especially singlet oxygen, is formed. These reactive oxygen species damage cell components, leading eventually to cell death via apoptosis or necrosis. À large number of naturally occurring and synthetic dyes have been evaluated as potential photosensitizers for photodynamic therapy. Perhaps the most widely studied photosensitizers are the tetrapyrrolic macrocyclic compounds. Among them, especially porphyrins and chlorins have been tested for their PDT efficacy. Porphyrins are macrocyclic compounds with bridges of one carbon atom joining pyrroles to form a characteristic tetrapyrrole ring structure. There are many different classes of porphyrin derivatives including those containing dihydro- pyrrole units. Chlorins, as referred to in the present invention, are porphyrin derivatives containing one dihydro-pyrrole unit whereas bacteriochlorins are characterized by two dihydro-pyrrole units. In general, chlorins are characterized in that one double bond of the aromatic system in B-position is absent and bacteriochlorins are characterized in that two opposite double bonds are absent compared to the porphyrin. Methods to prepare chlorins are known in the art. They may e.g. be prepared by reduction of porphyrins (R. Bonnett et al., Biochem. J. 1989, 261, 277-280) or by oxidative dihydroxylation of porphyrins (C. Brückner, D. Dolphin, Tetrahedron Lett. 1995, 36, 3295-3298; J. K. MacAlpine et al., J. Porphyrins Phthalocyanines 2002, 6, 146-155).

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P 106691 LU101031 Examples of tetrapyrrolic macrocyclic compounds used as photosensitizers are described in US 2012/263,625 A1 from Aicher et al. which discloses glyco-substituted dihydroxy-chlorins for antibacterial PDT, US 7,022,843 B1 from MacAlpine et al. which provides B,f'-dinhydroxy meso-substituted chlorins as photosensitizers, and US 7,166,719 B2 from Pandey et al. which discloses tetrapyrrole compounds containing a fluorinated substituent where the compound is a chlorin or a bacteriochlorin for PDT diagnostic and therapeutic application. There are several properties that an effective photosensitizer should exhibit. Among them, a desirable characteristic in order to efficiently destroy deep target tissues is a strong absorption at long wavelength. Many current photosensitizers are not efficient enough as they have low absorption in the red region of the spectrum. Chlorins have the advantage that they possess an intense absorption in the red and near-infrared region of the electromagnetic spectrum. As light of longer wavelength penetrates deeper into the tissue, it is thus possible to treat e.g. more expanded tumors, if the PDT is employed for tumor therapy. Chlorins possessing potential for PDT can either be derived from natural sources or from total synthesis. Another requirement for an effective photosensitizer is the accumulation in the tumor tissue. Moreover, this accumulation should occur within cell structures that are sensitive to the oxidative damage. In order to achieve this it is generally accepted that photosensitizers for tumor therapy have to be amphiphilic compounds which facilitates their accumulation in membrane structures of the cells. In recent years the combination of tetrapyrrole photosensitizers with carbohydrates has intensively been investigated. One reason for this is that the decoration of the tetrapyrrole with carbohydrates is considered as a tool to increase their amphiphilicity (B. Chauvin et al., Eur. J. Pharm. Biopharm. 2013, 83, 244-252). Moreover, the connection of the photosensitizers with carbohydrates opens up the possibility to increase the photosensitizer accumulation in the tumor cells by specific interaction with receptors overexpressed in some types of malignant cells, such as lectin-type receptors (S. Ballut ef al., Org. Biomol. Chem. 2012, 10, 4485- 4495). For the connection of tetrapyrrole photosensitizers with carbohydrates a number of methods are known in the art, e.g. the glyco-substituted aldehydes may be condensed with pyrrole to form a glyco- substituted tetrapyrrole (P. Maillard et al., Tetrahedron Lett. 1992, 33, 8081-8084; K. Driaf et al., Tetrahedron Lett 1993, 34, 1027-1030; D. Ouimi et al., J. Org. Chem. 1995, 60, 1554-1564; Y. Mikata et al., Tetrahedron Lett. 1998, 39, 4505-4508; |. Laville et al., Bioorg. Med. Chem. 2004, 12, 3673-3682) or the glycosylation may be performed on the final tetrapyrrole (see e.g.: G. Fülling et al., Angew. Chem. Int. Ed. Engl. 1989, 28, 1519- 1521; J. P. C. Tomé et al., Bioorg. Med. Chem. 2005, 13, 3878-3888; D. Aicher et al, Synlett 2010, 395-398). These methods for preparing glycosylated porphyrins may be combined with the above-mentioned methods of preparing chlorins to obtain glycosylated chlorins or bacteriochlorins (I. Laville et al., Bioorg. Med. Chem. 2003, 11, 1643-1652).

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P 106691 LU101031 In the embodiments described in the art it is emphasized that tri- and tetraglycosylated or even higher glycosylated tetrapyrroles are especially active as photosensitizers (I. Lavilie et al., Bioorg. Med. Chem. 2003, 11, 1643-1652; Y. Mikata et al., Tetrahedron Lett. 1998, 39, 4505-4508; Laville, S. et al.. Bioorg. Med. Chem. 2004, 12, 3673-3682; |. Laville et al, Bioorg. Med. Chem. 2003, 11, 1643-1652; S. Ballut et al, Org. Biomol. Chem. 2012, 10, 4485-4495; B. Chauvin et al., Eur. J. Pharm. Biopharm. 2013, 83, 244-252). Objectives and Brief Summary of the Invention Nevertheless, there is still a desire for biologically active compounds that can be used as highly effective photosensitizers for a wide range of applications including light irradiation treatments, such as photodynamic therapy of cancer and other diseases, as well as for pharmaceutical compositions of such biologically active compounds. In particular, upon light irradiation the compounds should exhibit a strong phototoxicity rendering them suitable as photosensitizer for PDT. Furthermore, the compounds should easily be synthesized. These objects are surprisingly achieved by a tetrapyrrolic compound according to claims 1 to 12, a composition according to claims 13 to 15 and the use of the tetrapyrrolic compound according to claims 16 and 17. The tetrapyrrolic compounds according to the invention have a structure of Formula 1, 2 or 3: o-R' O~p1 r? Ro” NR B SP STE 2 ) NH N= 2 X NH ie \ B R À r2 R gr? n° NH N= 2 A HN / — HN / \ N HN 1 x FNS x CN N | CESAM 1 nr 2 R' 3 oO OR! wherein B is

H H ; J H H ; OH , OH, J NH Ih H ; OH J OH ; H ‘ H ; H “U N 7 or 7 , O-R' is a substituent in the meta or para position of the phenyl ring, = a

P 106691 LU101031 R' is a glyco-substituent derived from a mono-, di-, or trisaccharide group, and each R? is independently selected from the group consisting of a linear or branched (fluoro-)alky! group with 3 to 8 carbon atoms, phenyl, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1’-thio-g-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30, wherein (a) in Formula 1 or 2, if Bis , H

SSH N = O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched alkyl group with 5 to 8 carbon atoms, a linear or branched fluoroalkyl group with 3 to 8 carbon atoms, 3,5-bis(trifluoromethyl)phenyl, 4-(1’-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl, 4-(1’-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),,CH; with n = 1-30, (b) in Formula 1 or 2, if Bis , H

NH N== O-R' is a substituent in the para position of the phenyl ring and R' is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1’-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1'-thio-8-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30, 4/63 A

P 106691 LU101031 (c) in Formula 1 or 2, if O-R' is a substituent in the meta position of the phenyl ring and R' is glucosyl and R? is n-hexyl, phenyl or 3,5-bis(trifluoromethyl)phenyl, then B is

H PET ; OH „OH, A H OH / OH ’ H ‘ H A H 21° LT or , (d) in Formula 1 or 2, if O-R' is a substituent in the meta position of the phenyl ring and R' is galactosyl and R? is phenyl, then B is

H «Vu ; OH „OH,

K H A OH A OH z H e H 0 H "° 1° or oo , (e) in Formula 3, if Bis , H

SNH N= O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1'-thio-p-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyi, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH3 with n = 1-30, (f) in Formula 3, if B is , H ; H - H ’ H ; N= 5/63 EL 4

P 106691 LU101031 O-R' is a substituent in the meta position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyt, 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30, and (g) in Formula 3, if Bis , H

SNH N= O-R' is a substituent in the para position of the phenyl ring and R' is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-8-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-pheny! with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30.

Formulae 1, 2 and 3 as well as other formulae shown herein cover all stereoisomeric forms as well as mixtures of different stereoisomeric forms, such as e.g. racemates. The formulae cover only those compounds that are compatible with the chemical valence theory.

Detailed Description The biologically active tetrapyrrolic compounds of the present invention can be used as photosensitizer for a wide range of light irradiation treatments such as photodynamic therapy (PDT) of cancer and other hyperproliferative diseases.

Tetrapyrrolic compounds according to Formula 1, 2 or 3 are preferred, wherein (a) in Formula 1 or 2, if Bis 6/63 ZU

P 106691 LU101031 ; H

SN H N = O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched alkyl group with 5 to 8 carbon atoms, a linear or branched fluoroalkyl group with 3 to 8 carbon atoms, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl, and 4-(1’-thio-B-D-galactosyl)-2,3,5,6-tetra- fluorophenyl, (b) in Formula 1 or 2, if Bis ; H / N—H N== O-R' is a substituent in the para position of the phenyl ring and R' is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, and 4-(1’-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, (e) in Formula 3, if Bis ; H

SNH N= O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1’-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1’-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, (f) in Formula 3, if B is

P 106691 LU101031 ; H x H > H ’ H N= O-R' is a substituent in the meta position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyi group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, and 4-(1'-thio-8-D-galactosyl)-2,3,5,6-tetrafluorophenyl, or (g) in Formula 3, if Bis ; H

SNH N= O-R' is a substituent in the para position of the phenyl ring and R' is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-8-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl. Preferred compounds of Formula 1, 2 or 3 are: Ho HOO oH PH OH

N Q TO se O AA 0 ©

HO Fr

F FaC. F3 Oo on A OH CFs Ho oH a $C) CF, - = ;

O A FaC CF3 ’ F ’ 8/63 Z

P 106691 LU101031 F. F Ÿ Ho” Ca . x Ca F > F 2 Co SRL "D se LT” AL bec ÿ ÿ

OH ae U 0 = Orzo SLs OH HO OH © pe A Geof dom TOE IQ , J and

OH OH OR pe OH ue Particularly preferred compounds of Formula 1, 2 or 3 are: 9/63 ZZ. a

P 106691 LU101031 oH OH OH HO © 4 a CC SETZT Q HO: HO. CH

OH OH NR 0 OH

OÖ > 0 Ce ©. WL , and The compounds according to the invention are tetrakis-meso-substituted porphyrin and chlorin structures and it has unexpectedly been found that various porphyrins and chlorins containing one or two specific glycosylated residues in their meso positions are especially suited for such a medical application. They exhibit an unusually strong PDT activity compared to the corresponding tri- and tetraglycosylated tetrapyrroles, although the latter are usually considered as better photosensitizers. Furthermore, the new photosensitizers provided by the present invention have the advantage that they can easily be produced and characterized. Moreover, as the present invention provides methods to tailored amphiphilic compounds for desired PDT applications, target tissue selectivity and, therefore, PDT efficacy, is increased. R' is a glyco-substituent derived from a mono-, di-, or trisaccharide group. In particular, R'is a glyco- substituent selected from glycosyl groups of mono-, di-, or trisaccharides. In a preferred embodiment the glyco-substituent comprises a glycosy! group of a mono- or disaccharide derived from or consisting of naturally occurring monosaccharides or disaccharides as building blocks, such as in particular glucose, galactose, mannose, ribose, fructose, rhamnose, lactose, partially deoxygenated derivatives thereof, aminosugars, such as glucosamines or galactosamines, neuraminic acids and combinations thereof. Furthermore, in a preferred embodiment each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group having 3 to 8 carbon atoms, phenyl, pentafluorophenyl and 3,5- bis(trifluoromethyl)phenyl. Moreover, in a preferred embodiment each R? group of a compound according to the invention is the same R° group. 10/63 ZZ

P 106691 LU101031 In a further preferred embodiment R' is mannosyl or lactosyl and R° is a linear or branched (fluoro-)aikyl group with 3 to 8 carbon atoms, phenyl, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D- glucosyl)-2,3,5,6-tetrafluorophenyi or 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl. In another preferred embodiment B is ; H

INH N= O-R' is a substituent in the para position of the phenyl ring, R'is mannosy! or lactosyt and R? is phenyl. In yet another preferred embodiment in Formula 1 or 2 O-R' is a substituent in the meta position of the phenyl ring, R'is glucosyl and each R? is a linear or branched fluoroalkyl group with 3 to 8 carbon atoms, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl or 4-(1’-thio-B-D-galactosyl)- 2,3,5,6-tetrafluorophenyl. In a further preferred embodiment in Formula 3 B is , H

INH N= R' is glucosyl or galactosyl and each R? is a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1"-thio-B-D-glucosyl)-2,3,5,6-tetrafiuorophenyl or 4-(1"- thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl. In another preferred embodiment in Formula 1 or 2 B is

H ; OH + OH ° H N ——— R' is glucosyl or galactosy! and each R? is a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1"-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl or 4-(1”- thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl. 11/63

P 106691 LU101031 In a particular preferred embodiment in Formula 1 or 2 B is

H ; OH „A OH re H N — R'is glucosyl and each R? is a linear or branched alkyl group with 5 to 8 carbon atoms. In another preferred embodiment of the present invention O-R'isa glycosidic bond. In particular, a glycosidic bond is formed between the hemiacetal or hemiketal group of a saccharide or a molecule derived from a saccharide and the hydroxyl group of a precursor of the tetrapyrrolic compound, such as an alcohol. In a further preferred embodiment of the present invention R? is 4-(1'-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl or 4-(1’-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl. In a particularly preferred embodiment of the present invention in Formula 1 or 2 R'is glucosyl and R? is 4- (1’-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl or 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafiuoropheny!. The tetrapyrrolic compounds according to Formula 1, 2 or 3 have two or three R? substituents which can be the same or different. In a preferred embodiment, each R? of the compound according to the invention is the same. Moreover, the tetrapyrrolic compounds according to Formula 3, which have a ‘trans’ arrangement of meso- glyco-substituents, have two R' substituents which can be the same or different. In a preferred embodiment, each R of a compound of Formula 3 is the same. The tetrapyrrolic compounds according to the invention can be prepared by methods generally known in the art. For example, tetrapyrrolic compounds according to the invention can easily be synthesized by reacting a hydroxyphenyl-substituted tetrapyrrole with a corresponding glyco-trichloroacetimidate. In one embodiment of the present invention tetrapyrrolic compounds are provided combining two different kinds of glyco-substituents R'. For this purpose the glycosylation of tetrapyrroles via trichloroacetimidates as described in Aicher et al. (D. Aicher et al., Synlett 2010, 395-398) is combined with a nucleophilic aromatic substitution on pentafluorophenyl-substituted tetrapyrroles known from e.g. X. Chen et al., Biochem. 2004, 43, 10918-10929; S. Hirohara et al, Bioorg. Med. Chem. 2010, 18, 1526-1535; C. R. Becer et al, Macromolecules 2009, 42, 2387-2394. 1-thio-B-D-glucose, 1-thio-B-D-galactose, 1-thio-a-D-mannose and 12/63

P 106691 LU101031 their derivates bearing protective groups, such as acetyl groups, are preferred nucleophiles for the nucleophilic aromatic substitution on pentafluorophenyl residues. 1-thio-B-D-glucose, 1-thio-B-D-galactose and their derivates bearing protective groups, such as acetyl groups, are particularly preferred. In general, the novel photosensitizers having a structure of Formula 1, 2 or 3 according to the present invention can be synthesized by functionalizing tetrapyrrole compounds with the desired glyco-substituents (D. Aicher et al, Synlett 2010, 395-398). These glyco-modified compounds can further be converted to simple chlorins or dihydroxy-chlorins (see EP 0337601 B1; WO 09/613504 A1, WO 00/061584 A1; C. Brückner, D. Dolphin, Tetrahedron Lett. 1995, 36, 3295-3298; C. Brickner, D. Dolphin, Tetrahedron Lett. 1995, 36, 9425-9428; H. W. Daniell et al., Tetrahedron Lett. 2003, 44, 4045-4049; F. Rancan et al, J. Photochem. Photobiol. B: Biology 2005, 78, 17-28; D. Aicher et al, Bioorg. Med. Chem. Lett. 2011, 21, 5808-5811). As used herein, mono- and di-glycosylated tetrapyrrolic compounds according to the invention are also referred to as unsymmetrical porphyrins and chlorins. Acceptable starting materials for the synthesis of the unsymmetrical porphyrins and chlorins according to the present invention can be pyrrole and aldehydes. More specifically, pyrrole and two aldehydes are typically employed for the synthesis of the unsymmetrically substituted porphyrins. In particular, pyrrole and aldehydes are subjected to a condensation reaction. Suitable methods for this condensation are known in the art (J. S. Lindsey et al., J. Org. Chem. 1987, 52, 827-836). Alternatively, the unsymmetrically substituted porphyrins can also be synthesized using di- or tripyrromethanes and aldehydes, as is also known in the art (C.-H. Lee et al., Tetrahedron 1994, 50, 11427— 11440). After condensation, purification and deprotection at their hydroxyl groups the desired unsymmetrically substituted porphyrins are modified at their hydroxyphenyl substituents (either 3- hydroxyphenyl or 4-hydroxyphenyl) with the glyco-trichloroacetimidates as glycosyl donors. After purification of the modified porphyrins, these can, if desired, be converted to the corresponding chlorins. In one embodiment of the present invention a glyco-substituted porphyrin is synthesized and converted to the corresponding chlorin system by dihydroxylation or reduction, preferably dihydroxylation. Dihydroxylation using osmium tetroxide is particularly preferred. In a specifically preferred embodiment of the present invention a porphyrin of the ‘trans-AzBz-type is synthesized, having a glyco-substituent as substituent A and an alkyl! or fluoroalkyl groups or (substituted) phenyl rings as substituent B. This porphyrin again can easily be converted to the chlorin and the dihydroxychlorin with the methods known in the art. Furthermore, the present invention is directed to a pharmaceutical composition comprising a tetrapyrrolic compound according to the invention.

13/63 FC re

P 106691 LU101031 The tetrapyrrolic compounds disclosed in the present invention are mostly lipophilic compounds because such compounds have a higher tendency to accumulate in cellular membrane structures. It is in these membrane structures where the reactive oxygen species generated by the photodynamic treatment can effectively damage the (tumor) cells. However, due to their lipophilic nature photosensitizers are sparingly or not at all water soluble so suitable pharmaceutical formulations are needed for their clinical application. Such pharmaceutical formulations may involve liposomal, nanoparticle or polymer-based formulations. For increasing patient compliance during treatment improved formulations of photosensitizers e.g. oral formulations are needed. Accordingly, liposomal formulations comprising the tetrapyrrolic compound according to the invention are preferred. Liposomal formulations comprising the tetrapyrrolic compound according to the invention and further comprising PLGA particles, HSA particles, cyclodextrines and/or polymer particles are particularly preferred. Liposomal formulations as stated above conjugated to a targeting agent, preferably an antibody or a fragment thereof, are most preferred. In this respect, WO 2011/071970 A2 by Langer et al. discloses suitable photosensitizer formulations based on poly-lactic-co-glycolic-acid (PLGA) whereas WO 2011/071968 A2 by Langer et al. discloses formulations based on human serum albumin (HSA) nanoparticles. Furthermore, WO 2005/023220 A1 by Albrecht et al. discloses suitable liposomal formulations. Possible oral formulations for such photosensitizers are described in WO 2010/129337 A2 by Graefe et al. and in WO 2010/129340 A2 by Farmer et al. Typically, PDT is accomplished by first incorporating the compound according to the invention into a pharmaceutically acceptable application vehicle (e.g. ethanolic solution, liposomal formulation or a formulation based on HSA or PLGA particles) for delivery of the tetrapyrrolic compound to a specific treatment site. After administering the tetrapyrrolic compound in the vehicle to a treatment area, sufficient time is allowed so that the tetrapyrrolic compound preferentially accumulates in the diseased tissue. Lastly, the treatment area is irradiated with light of a proper wavelength and sufficient power to activate the porphyrin derivatives to induce necrosis or apoptosis in the cells of said diseased tissue. Thus, one of the main advantages is that convenient pharmaceutical formulations can be created for the biologically active tetrapyrrolic compounds of the present invention such as liposomal formulation to be injected avoiding undesirable effects like precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems. Due to their amphiphilic nature, the chemically stable porphyrin and chlorin derivatives of the present invention can be prepared in various pharmaceutically acceptable and active preparations for different administration methods, e.g. injections. In a specifically preferred embodiment such amphiphilic compounds are formulated into liposomes. This liposomal formulation can then be injected avoiding undesirable effects such as precipitation at the injection site or delayed pharmacokinetics of the tetrapyrrole systems. Hence, the tetrapyrrolic compounds according to the invention are suitable for use in medical applications such as photodynamic therapy, in particular photodynamic therapy of tumors and other hyperproliferative 14/63 FE

CE

P 106691 LU101031 diseases, dermatological disorders, ophthalmological disorders, urologicai disorders, arthritis and other inflammatory or hyperproliferative diseases. Accordingly, a method of photodynamic therapy, in particular photodynamic therapy of tumors and other hyperproliferative diseases, dermatological disorders, ophthalmological disorders, urological disorders, arthritis and other inflammatory or hyperproliferative diseases comprising administering a tetrapyrrolic compound according to the invention or a pharmaceutical composition thereof to a patient in need thereof, is also disclosed herein. Furthermore, the tetrapyrrolic compounds according to the invention are suitable for use in diagnosis, in particular fluorescence diagnosis. The following examples are presented to provide those of ordinary skill in the art with a full and illustrative disclosure and description of how to make the porphyrin and chlorin derivatives of the invention and show their photodynamic activity and are not intended to limit the scope of what the inventor regards as the invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature etc), but some experimental errors and deviations should be accounted for. Also, best measures have been taken to name the compounds with their systematic IUPAC name, nevertheless the basic reference are the given structural formulas based on the experimental spectroscopic data. Brief Description of Figures Figure 1 shows the results of the cell test of 5,15-bis-(4-B-D-glucosylphenyl)-10,20-dihexylporphyrin with the cell lines A431, CAL-27, L929 and HT29 (Example 4.1). Figure 2 shows the results of the cell test of 5,15-bis-(4-B-D-galactosylphenyl)-10,20-dihexylporphyrin with the cell lines A431, A253, CAL-27, L929 and HT29 (Example 4.2). Figure 3 shows the results of the cell test of 5-(4-B-D-lactosylphenyl)-10,15,20-triphenylporphyrin with cell lines A431, A253, CAL-27, L929 and HT29 (Example 4.3). Figure 4 shows the results of the cell test of 5-(3-B-D-glucosylphenyl)-10,15,20-trihexyi-17,18-dihydroxy- 17,18-chlorin with the cell lines A431 and CAL-27 (Example 4.4). Figure 5 shows the results of the cell test of 5-(3-B-D-glucosylphenyl)-10,15,20-tris-(4-1"-thio-B-D-glucosyl- 2,3,5,6-tetrafluorophenyl)-porphyrin with the cel! lines A 253, CAL-27, L929 (Example 4.5). Figure 6 shows the results of the cell test of 5,10,15-tris-(3-B-D-galactosylphenyl)-20-[3,5-bis-(trifluoromethyl)- phenyl]-17,18-dihydroxy-17,18-chlorin with the cell line HT29 (Reference Example 4.6).

15/63 ZZ =

P 106691 LU101031 Figure 7 shows the results of the cell test of 5,10,15-tris-(3-B-D-lactosylphenyl)-20-[3,5-bis-(trifluoromethyl)- phenyl]-17,18-dihydroxy-17,18-chlorin with the cell line HT29 (Reference Example 4.7). Figure 8 shows the results of the cell test of 5,10,15,20-tetrakis-(3-B-D-galactosyl)-porphyrin with the cell lines A431, A253, CAL-27, L929 and HT29 (Reference Example 4.8). Figure 9 shows the results of the cell test of 5,10,15,20-tetrakis-(4-B-D-glucosyl)-porphyrin with the cell lines A431, A253 and HT29 (Reference Example 4.9). Examples All reagents were used as purchased from commercial suppliers. Dichloromethane was purified by distillation over K,COs prior to use. Thin layer chromatography (TLC) was performed using Merck silica gel 60 (without fluorescence indicator) pre-coated on aluminum sheets. Flash chromatography was carried out using Fluka silica gel 60, 0.040-0.063 mm (230-400 mesh). 'H and ‘’C NMR spectra were recorded in CDCl,, (CD3),CO, CD3OD or {CD3),SO on Bruker (AC 500 and AVIII 700) and JOEL (Eclipse 500) instruments. Chemical shifts 0 are given in ppm relative to TMS as internal standard or relative to the resonance of the residual solvent peak, J values are given in Hz. Mass spectra were recorded on an Agilent 6210 ESI-TOF, Agilent Technologies, Santa Clara, CA, USA. Electronic absorption spectra were recorded on a Specord S300 (Analytik Jena) spectrophotometer using dichloromethane, ethanol, acetone or dimethyl sulfoxide as solvent. Example 1 - Preparation of glycosubstituted porphyrins

1.1 Preparation of 5-[4-(2,3,4,6-tetraacetyl-a-D-mannosyl)phenyl]-10,15,20-triphenylporphyrin In a typical experiment, under argon atmosphere, Zn(ll)-5-(4-hydroxyphenyl)-10,15,20-triphenylporphyrin (100 mg, 144 umol) was dissolved in 20 ml dry dichloromethane and 0.5 mi dry acetonitrile. Then, 2,3,4,6- tetraacetyl-a-D-mannose trichloroacetimidate (862 mg, 1.75 mmol) and BF3-Et;O (7.5 pl, 60 umol) were added. After stirring for 3 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 100 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 20 ml tetrahydrofuran, and 0.6 ml of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (100 ml) and dichloromethane (150 ml) were added. The organic layer was separated and washed with water (2 x 100 mi). After drying with Na,SO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/methanol 95:5 as the eluent. The analytically pure product (108 mg, 78%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol.

16/63 FC or

P 106691 LU101031 > ( a DO ©

ARO mp: > 300 °C, 'H NMR (700 MHz, (CD;),CO): à = -2.73 (br s, 2 H, NH), 2.04 (s, 3 H, OAc), 2.06 (s, 3 H, OAc), 2.13 (s, 3 H, OAc), 2.24 (s, 3 H, OAc), 4.25 (dd, J = 2.8, 12.3 Hz, 1 H, H-6,‘ose'), 4.37 (dd, J = 6.4,

12.3 Hz, 1 H, H-6g'ose"), 4.45 (ddd, J = 2.8, 6.4, 10.0 Hz, 1 H, H-5‘ose’), 5.46 (dd, J = 10.0, 10.0 Hz, 1 H, H- 4‘ose”), 5.64 (dd, J = 1.9, 3.8 Hz, 1 H, H-2‘ose”), 5.69 (dd, J = 3.8, 10.0 Hz, 1 H, H-3'ose’), 6.02 (d, J = 1.9 Hz, 1 H, H-1‘ose’), 7.62 (d, J = 8.7 Hz, 2 H, Ar-Hreta), 7.79-7.82 (m, 9 H, 6 x Ph-Hreta, 3 X Ph-Hpara), 8.21 (d, J =

8.7 Hz, 2 H, Ar-Horno), 8-23-8.25 (m, 6 H, Ph-Hono), 8.86 (s, 6 H, 8-H), 8.90 (d, J = 4.3 Hz, 2 H, B-H) ppm. °C NMR (176 MHz, (CD3),CO): à = 21.69 (q, OCHz), 21.73 (gq, OCHz), 21.76 (q, OCHz), 21.80 (q, OCHz), 64.21 (t, C-B'ose’), 67.86 (d, C-4'ose”), 70.96 (d, C-3'ose’), 71.12 (d, C-5'0se’), 71.58 (d, C-2'ose'), 98.33 (d, C- d‘ose’), 117.32 (d, Ar-Creta). 121.51 (s, Ar-Creso), 122.10 (s, Ph-Creso), 122.14 (s, Ph-Creso). 128.76 (d, Ph- Creta), 129.86 (d, Ph-Cpara), 136.32 (d, Ar-Corno), 137.37 (d, Ph-Cormno), 144.88 (Ss, Ph-C;pso), 157.82 (s, Ar- Coman), 171.36 (s, C=0), 170.45 (s, C=0), 170.51 (s, C=0), 170.71 (s, C=0) ppm. ESI-HRMS: CsgH49N4040 * (IM + HY"): calculated 961.3448, found 961.3444. UV/vis (CHzCl2): Amax (log eldm® mor” em”) : 415 (5.51), 513 (4.30), 547 (4.00), 591 (3.84), 647 (3.66) nm.

1.2 Preparation of 5-[4-(2,3,4,6,2',3’,6’-heptaacetyl-B-D-lactosyl)phenyl]-10,15,20-triphenylporphyrin In a typical experiment, under argon atmosphere, Zn(ll)-5-(4-hydroxyphenyl)-10, 15,20-triphenylporphyrin (60 mg, 86 pmol) was dissolved in 10 mi dry dichloromethane and 0.5 mi dry acetonitrile. Then, 2,3,4,6,2’,3’,6’- heptaacetyl-a-D-lactose trichloroacetimidate (500 mg, 640 pmol) and BF; Et,O (10 ul, 80 umol) were added. After stirring for 2 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 100 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 20 ml tetrahydrofuran, and 0.6 mi of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (100 ml) and dichloromethane (150 ml) were added. The organic layer was separated and washed with water (2 x 100 ml). After drying with NazSO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/methanol 99:1 as the eluent. The analytically pure product (58 mg, 54%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. 17/63 GE A 7

P 106691 LU101031 Ce OAc Aen oD) © - one " one sue mp: > 300 °C, 'H NMR (700 MHz, CDCIs): 5 = -2.80 (br s, 2 H, NH), 1.99 (s, 3 H, OAc), 2.09 (s, 3 H, OAc),

2.11 (s, 3 H, OAc), 2.13 (s, 3 H, OAc), 2.15 (s, 3 H, OAc), 2.19 (s, 3 H, OAc), 2.21 (s, 3 H, OAc), 3.96-4.04 (m, 3 H, H-5"ose’, H-4"ose’, H-5‘ose”), 4.16 (dd, J = 7.3, 11.2 Hz, 1 H, H-6,0se"), 4.22 (dd, J = 6.3, 11.2 Hz, 1 H, H-Bg'ose’), 4.29 (dd, J = 5.7, 11.9 Hz, 1 H, H-65 ose"), 4.58 (d, J = 7.9 Hz, 1 H, H-t'ose’), 4.62 (dd, J =

2.0, 11.9 Hz, 1 H, H-65 ose’), 5.00 (dd, J = 3.4, 10.4 Hz, 1 H, H-3'ose”), 5.18 (dd, J = 8.0, 10.4 Hz, 1 H, H- 2'ose’), 5.39-5.47 (m, 4 H, H-4'ose’, H-1"ose', H-2"ose', H-3"0se"), 7.38 (d, J = 8.5 Hz, 2 H, Ar-Hreta), 7.76-

7.83 (m, 9 H, 6 x Ph-Hreta, 3 X Ph-Hpara), 8.15 (d, J = 8.5 Hz, 2 H, Ar-H), 8.21-8.24 (m, 6 H, Ph-Homo),

8.81-8.84 (m, 8 H, B-H) ppm. "°C NMR (176 MHz, CDCIs): & = 20.55 (q, CHz), 20.68 (q, CHz), 20.69 (q, CH),

20.71 (q, CHz), 20.87 (gq, CHz), 20.89 (q, CHz), 60.90 (t, C-G'ose”), 62.27 (t, C-6 ose’), 66.68 (d, C'ose’),

69.17 (d, C-2’ose’), 70.85 (d, C'ose’), 71.02 (d, C-3'ose’), 71.70 (d, C'ose’), 72.97 (d, C'ose’), 73.10 (d, C'ose’), 76.45 (d, C'ose’), 98.95 (d, C-1"ose’), 101.25 (d, C-1‘ose’), 115.05 (d, Ar-Creta), 119.17 (s, Ar-Cmeso),

120.20 (s, Ph-Creso), 120.22 (s, Ph-Creso), 126.70 (d, Ph-Creta), 127.75 (d, Ph-Cpara), 134.56 (d, Ph-Cortno).

135.56 (d, Ar-Cortho), 137.25 (s, Ar-Cipso), 142.14 (s, Ph-C;pso), 156.64 (s, Ar-Corac), 169.15 (s, C=0), 169.78 (s, C=0), 169.84 (s, C=0), 170.08 (s, C=0), 170.17 (s, C=0), 170.37 (s, C=0), 170.40 (s, C=O) ppm. ESI- HRMS: C7oHesN4O48 * ([M + HJ’): calculated 1249.4294, found 1249.4248. UV/vis (CH2Cl2): Amax (log &/dm° mol” em”) : 418 (5.56), 515 (4.26), 550 (3.94), 590 (3.81), 647 (370) nm.

1.3 Preparation of 5-[4-(2,3,4,6-tetraacetyl-B-D-glucosyl)phenyl]-10,15,20-tris-[3,5-bis-(trifluoro- methyl)phenyl]-porphyrin In a typical experiment, under argon atmosphere, Zn(ll)-5-(4-hydroxyphenyl)-10,15,20-tris-[3,5-bis- (trifluoromethyl)pheny!]-porphyrin (50 mg, 43 pmol) was dissolved in 10 ml dry dichloromethane. Then, 2,3,4 6-tetraacetyl-D-glucose trichloroacetimidate (40 mg, 81 pmol) and BF; Et;0 (20 pl, 0.2 mmol) were added. After stirring for 20 minutes, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 10 ml tetrahydrofuran, and 1.0 mi of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (50 ml) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 ml). After drying with Na,SO,, the solvent was evaporated under 18/63 77 IL &_

P 106691 LU101031 reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/ethyl acetate 95:5 as the eluent. The analytically pure product (49 mg, 83%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. FiC O CF; OAc CF3 ex oO CQ OAc CF, FC € CF3 mp: 154 °C, "H NMR (500 MHz, CDCIs): à = -2.84 (brs, 2 H, NH), 2.11 (s, 3 H, OAc), 2.12 (s, 3 H, OAc), 2.13 (s, 3 H, OAc), 2.23 (s, 3 H, OAc), 4.08 (ddd, J = 2.5, 5.3, 10.0 Hz, 1 H, H-5‘ose’), 4.33 (dd, J = 2.5, 12.4 Hz, 1 H, H-6,‘ose'), 4.43 (dd, J = 5.3, 12.4 Hz, 1 H, H-6g‘ose’), 5.33 (dd, J = 9.5, 10.0 Hz, 1 H, H-4'ose'), 5.47 (dd, J = 9.5, 9.5 Hz, 1 H, H-3'ose'), 5.49 (d, J = 7.7 Hz, 1 H, H-1'0s¢’), 5.50-5.53 (m, 1 H, H-2‘ose’), 7.44 (d, J = 8.5 Hz, 2 H, 2 x Ar-Hreta), 8.16 (d, J = 8.5 Hz, 2 H, 2 x Ar-Hortho), 8.38 (brs, 3 H, 3 x Arr-Hpara), 8.70 (brs, 6 H, 6 x Arr-Hortho), 8.75 (d, J = 4.8 Hz, 2 H, 6-H), 8.79 (s, 4 H, &-H), 8.99 (d, J = 4.8 Hz, 2 H, 6-H) ppm. °C NMR (126 MHz, CDCl): à = 20.74 (q, OCHz), 20.78 (q, OCHz), 20.86 (gq, OCHj3), 20.91 (gq, OCHz), 62.16 (t, C-G'ose'),

68.43 (d, C-4'ose”), 71.39 (d, C-2'ose’), 72.44 (d, C-5'0se’), 72.88 (d, C-3'ose'), 99.19 (d, C-1'ose’), 115.40 (d, Ar-Creta), 116.77 (s, Arr-Crmeso), 117.19 (S, Arr-Crmeso). 120.31 (S, Arr-Creso), 121.59 (s, Ar-Creso), 122.27 (d, Arr-Cpara), 122.48, 124.65, 126.82, 130.62 (q, CF3), 130.65 (q, CF3), 133.77 (d, Are-Corno), 133.80 (d, Arç- Cortho), 135.75 (d, Ar-Cortho), 136.37 (s, Ar-Cjpso), 143.84 (s, Arr-Cjpso). 143.91 (8, Arr-Cpso), 157.05 (s, Ar- Coa), 169.56 (s, C=0), 170.44 (s, C=0), 169.56 (s, C=0) ppm. "“F-NMR (471 MHz, CDCly): à = -62.26 (s, 18 F, 6 x CF3) ppm. ESI-HRMS: CeaHasF18N4O10 “ (IM + HY"): calculated 1369.2692, found 1369.2683. UV/vis (CH,Cly): Amax (log e/dm* mor! em™): 420 (5.50), 515 (3.93), 554 (4.53), 593 (4.20), 645 (3.84) nm.

1.4 Preparation of 5,15-bis-[3-(2,3,4,6-tetraacetyl-B-D-glucosyl)-pheny!]-10,20-dihexylporphyrin In a typical experiment, under argon atmosphere, Zn(ll)-5,15-bis-(3-hydroxyphenyl)-10,20-dihexylporphyrin (75 mg, 0.10 mmol) was dissolved in 20 ml dry dichloromethane and 0.5 ml dry acetonitrile. Then, 2,3,4,6- tetraacetyl-D-glucose trichloroacetimidate (250 mg, 507 pmol) and BF; -Et,O (5.0 pl, 40 pmol) were added. After stirring for 2 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 20 mi tetrahydrofuran, and 1.0 ml of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (50 ml) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 ml). After drying with Na,SO,, the solvent was evaporated under 19/63 22,

P 106691 LU101031 reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/ethyl acetate 95:5 as the eluent. The analytically pure product (108 mg, 78%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. OAc oO AcO oo

OO J Le Lex AcO OAc AcO mp: 205 °C, 'H NMR (500 MHz, CDCIs): 6 = -2.72 (m, 2 H, NH), 0.91-0.96 (m, 6 H, 2 x CHz), 1.31 (s, 3 H, OAc), 1.32 (s, 3 H, OAc), 1.36-1.43 (m, 4 H, 2 x CH), 1.48-1.57 (m, 4 H, 2 x CH2), 1.77-1.84 (m, 4 H, 2 x CH), 1.98 (s, 6 H, 2 x OAc), 2.04 (s, 6 H, 2 x OAc), 2.11 (s, 6 H, 2 x OAc), 2.47-2.57 (m, 4 H, 2 x CH2), 3.76-

3.80 (m, 2 H, H-5’ose’), 4.03-4.07 (m, 2 H, H-Ga'ose"), 4.14-4.19 (m, 2 H, H-6g'ose"), 4.93-5.00 (m, 4 H, 2 x CH), 5.18 (dd, J = 9.3, 9.3 Hz, 2 H, H-4’ose’), 5.32 (dd, J = 9.3, 9.3 Hz, 2 H, H-3'ose"), 5.36 (d, J = 7.9 Hz, 2 H, H-l’ose’), 5.41 (dd, J = 7.9, 9.3 Hz, 2 H, H-2'ose”), 7.43-7.46 (m, 2 H, Ar-H), 7.65-7.69 (m, 2 H, Ar-H),

7.84-7.87 (m, 2 H, Ar-H), 7.92-7.95 (m, 2 H, Ar-H), 8.89 (d, J = 4.7 Hz, 4 H, B-H), 9.42-9.46 (m, 4 H, ß-H) ppm. °C NMR (126 MHz, CDCl): & = 14.22 (q, CHz), 19.96 (q, OCHz), 20.60 (q, OCHz), 20.69 (q, OCHz),

20.80 (q, OCHsz), 22.80 (t, CHz), 30.32 (t, CHz), 31.99 (t, CHz), 35.42 (t, CH), 38.87 (t, CH), 61.98 (t, C- 6'ose’), 68.38 (d, C-4’ose’), 71.39 (d, C-2'ose'), 72.26 (d, C-B'ose'), 72.89 (d, C-3'ose'), 99.38 (d, C-1'ose’),

116.71 (d, Ar-C), 118.10 (s, Ar-Crmeso), 120.19 (s, Ar-Creso). 122.78 (d, Ar-C), 127.67 (d, Ar-C), 129.95 (d, Ar- C), 144.32 (s, Ar-Cjpso), 155.35 (s, Ar-Cocu), 169.45 (C=0), 170.31 (C=0), 170.46 (C=0) ppm. ESI-HRMS: C72H83N4O20” ([M + HJ"): calculated 1323.5601, found 1323.5578. UV/vis (CHCl): Amax (log g/ldm® mol” em”): 419 (5.59), 518 (4.28), 554 (4.03), 597 (3.71), 653 (3.81) nm.

1.5 Preparation of 5,15-bis-[4-(2,3,4,6-tetraacetyl-B-D-glucosyl)-phenyl]-10,20-dihexylporphyrin In a typical experiment, under argon atmosphere, Zn(l1)-5,15-bis-(4-hydroxyphenyl)-10,20-dihexyiporphyrin (75 mg, 0.10 mmol) was dissolved in 20 mi dry dichloromethane and 0.5 ml dry acetonitrile. Then, 2,3,4,6- tetraacetyl-D-glucose trichloroacetimidate (250 mg, 507 pmol) and BF3-Et,O (5.0 pl, 40 pmol) were added. After stirring for 2 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 20 mi tetrahydrofuran, and 1.0 ml of hydrochloric acid (25%) were added. After 20/63 ZZ

P 106691 LU101031 stirring for 10 minutes, water (50 ml) and dichloromethane (75 mi) were added. The organic layer was separated and washed with water (2 x 50 mi). After drying with Na,SO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/ethy! acetate 95:5 as the eluent. The analytically pure product (113 mg, 82%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. OAc Lr fF 3 Ogre AcO AcO OAc OAc AcO mp: 204 °C, 'H NMR (500 MHz, CDCIs): 6 = -2.70 (br s, 2 H, NH), 0.91 (t, J = 7.5 Hz, 6 H, 2 x CH), 1.33-1.41 (m, 4 H, 2 x CH), 1.46-1.52 (m, 4 H, 2 x CH), 1.75-1.81 (m, 4 H, 2 x CH3), 2.11 (s, 6 H, 2 x OAc), 2.12 (s, 6 H, 2 x OAc), 2.14 (s, 6 H, 2 x OAc), 2.24 (s, 6 H, 2 x OAc), 2.47-2.53 (m, 4 H, 2 x CH), 4.07 (ddd, J = 2.4,

5.5, 10.2 Hz, 2 H, 2 x H-5‘ose”), 4.32 (dd, J = 2.4, 12.3 Hz, 2 H, 2 x H-6,'0se’), 4.44 (dd, J = 5.5, 12.3 Hz, 2 H, 2 x H-6g'ose’), 4.92-4.97 (m, 4 H, 2 x CH2), 5.32 (dd, J = 9.4, 10.1 Hz, 2 H, 2 x H-4'ose’), 5.45-5.53 (m, 6 H, 2 x H-1‘ose’, 2 x H-2'ose’, 2 x H-3'0ose’), 7.38 (d, J = 8.5 Hz, 4 H, Ar-Hreta), 8.14 (d, J = 8.5 Hz, 4 H, Ar-Hertho),

8.85 (d, J = 4.8 Hz, 4 H, 6-H), 9.42 (d, J = 4.8 Hz, 4 H, 8-H) ppm. BC NMR (126 MHz, CDCly): 6 = 14.11 (q, CHz), 20.64 (q, OCHz), 20.72 (q, OCHz), 20.82 (gq, OCHs), 22.69 (t, CHy), 30.32 (t, CH,), 31.89 (t, CH2), 35.31 (t, CHz), 38.68 (t, CH,), 62.14 (t, C-6'0se’), 68.46 (d, C-4'ose’), 71.38 (d, C-2'ose'), 72.32 (d, C-5'ose’), 72.89 (d, C-3'ose’), 99.30 (d, C-1‘ose’), 114.93 (d, Ar-Creta), 117.96 (s, Ar-Creso), 119.93 (8, Ar-Creso), 135.40 (d, Ar-Cortno), 137.79 (s, Ar-Cpso), 156.57 (s, Ar-Cocw), 169.48 (s, C=O), 170.35 (s, C=0), 170.65 (s, C=0) ppm. ESI-HRMS: C7,HgsNsOz (IM + HJ): calculated 1323.5601, found 1323.5572. UV/vis (CH,Cl): Amax (log e/dm* mor! cm”): 419 (5.59), 518 (4.28), 554 (4.03), 597 (3.71), 653 (3.81) nm.

1.6 Preparation of 5,15-bis-[4-(2,3,4,6-tetraacetyl-B-D-galactosyl)-phenyl]-10,20-dihexylporphyrin In a typical experiment, under argon atmosphere, Zn(ll)-5,15-bis-(4-hydroxyphenyl)-10,20-dihexylporphyrin (50 mg, 69 umol) was dissolved in 15 ml dry dichloromethane and 0.3 ml dry acetonitrile. Then, 2,3,4,6- tetraacetyl-D-galactose trichloroacetimidate (165 mg, 335 jmol) and BF3-Et,O (5.0 pl, 40 umol) were added. After stirring for 2 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the 21/63 Fe

P 106691 LU101031 residue was dissolved in 10 ml tetrahydrofuran, and 0.7 ml of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (50 ml) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 ml). After drying with Na,SO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/ethyl acetate 95:5 as the eluent. The analytically pure product (73 mg, 80%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. OAc PAC A0 tr Oza OAc AO ac mp: 161 °C, 'H NMR (500 MHz, CDCIs): à = -2.70 (br s, 2 H, NH), 0.91 (t, J = 7.4 Hz, 6 H, 2 x CHa), 1.34-1.41 (m, 4 H, 2 x CH), 1.46-1.54 (m, 4 H, 2 x CH), 1.76-1.82 (m, 4 H, 2 x CH,), 2.07 (s, 6 H, 2 x OAc), 2.08 (s, 6 H, 2 x OAc), 2.24 (s, 6 H, 2 x OAc), 2.27 (s, 6 H, 2 x OAc), 2.47-2.53 (m, 4 H, 2 x CH), 4.22-4.26 (m, 2 H, 2 x H-5‘ose’), 4.29-4.39 (m, 4 H, 2 x H-6‘ose’), 4.94-4.96 (m, 4 H, 2 x CH,), 5.28 (dd, J = 3.6, 10.0 Hz, 2 H, 2 x H- 3‘ose’), 5.41 (d, J = 8.2 Hz, 2 H, 2 x H-1‘ose’), 5.57 (dd, J = 0.9, 3.6 Hz, 2 H, 2 x H-4’ose’), 5.71 (dd, J = 8.2,

10.0 Hz, 2 H, 2 x H-2'0se’), 7.40 (d, J = 8.4 Hz, 4 H, Ar-Hrreta), 8.12 (d, J = 8.4 Hz, 4 H, Ar-Hortho), 8.86 (d, J =

4.8 Hz, 4 H, B-H), 9.42 (d, J = 4.8 Hz, 4 H, 8-H) ppm. "°C NMR (126 MHz, CDCls): 6 = 14.20 (q, CHz), 20.74 (q, OCHz), 20.79 (q, OCHj3), 20.83 (gq, OCHz), 21.02 (gq, OCH3), 22.78 (t, CH;), 30.29 (t, CHz), 31.98 (t, CH,),

35.40 (t, CH»), 38.78 (t, CH), 61.63 (t, C-6'0se’), 67.13 (d, C-4'ose”), 68.96 (d, C-2’ose’), 71.10 (d, C-3'ose"),

71.41 (d, C-5'0se’), 99.94 (d, C-1’0se’), 115.05 (d, Ar-Creta), 118.08 (s, Ar-Creso), 120.01 (s, Ar-Creso), 135.48 (d, Ar-Cortno), 137.85 (s, Ar-Cjpso), 156.70 (s, Ar-Cocai), 169.63 (s, C=O), 170.30 (s, C=O), 170.40 (s, C=0),

170.50 (s, C=0) ppm. ESI-HRMS: C72Hg3N4020" (IM + HJ): calculated 1323.5601, found 1323.5558. UV/vis (CH2C12): Amax (log e/dm* mor! cm”): 419 (5.60), 519 (4.26), 554 (4.02), 597 (3.69), 654 (3.80) nm.

1.7 Preparation of 5,15-bis-[3-(2,3,4,6-tetraacetyl-B-D-glucosyl)-phenyl]-10,20-diphenylporphyrin In a typical experiment, under argon atmosphere, Zn{ll)-5,15-bis-(3-hydroxyphenyl)-10,20-diphenylporphyrin (20 mg, 28 pmol) was dissolved in 4 ml dry dichloromethane and 0.2 ml dry acetonitrile. Then, 2,3,4,6- tetraacetyl-D-glucose trichloroacetimidate (50 mg, 102 pmol) and BF3-Et,O (1.0 pi, 8.0 pmol) were added. After stirring for 2 hours, the mixture was transferred to a separatory funnel. The organic layer was washed 22/63 ZZ / Sh

P 106691 LU101031 with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 4 mi tetrahydrofuran, and 0.2 ml of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (50 mi) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 ml). After drying with Na,SO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/ethyl acetate 95:5 as the eluent. The analytically pure product (28 mg, 75%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. OAc O

AN OAc a © AcO OAc J AcO mp: > 300 °C, 'H NMR (500 MHz, CDCIs): à = -2.83 (br s, 2 H, NH), 1.31-1.34 (m, 6 H, 2 x OAc), 1.97-1.98 (m, 6 H, 2 x OAc), 2.03 (m, 6 H, 2 x OAc), 2.09 (s, 6 H, 2 x OAc), 3.76-3.80 (m, 2 H, H-5‘ose’), 4.00-4.04 (m, 2 H, H-Bx‘ose’), 4.13-4.17 (m, 2 H, H-6g‘ose"), 5.13-5.18 (m, 2 H, H-4'ose’), 5.29-5.40 (m, 6 H, H-T'ose’, H- 2‘ose’, H-3'ose’), 7.41-7.44 (m, 2 H, Ar-H), 7.64-7.69 (m, 2 H, Ar-H), 7.75-7.79 (m, 6 H, 4 x Ph-Hreta, 2 x Ph- Hpara), 7.85-7.88 (m, 2 H, Ar-H), 7.93-7.96 (m, 2 H, Ar-H), 8.16-8.23 (m, 4 H, Ph-Homo), 8.84-8.88 (m, 8 H, B- H) ppm. °C NMR (126 MHz, CDCIs): & = 19.99 (q, CHa), 20.63 (q, CHa), 20.70 (q, CHa), 20.81 (q, CHa),

61.96 (t, C-6'0se’), 68.30 (d, C-4'ose'), 71.30 (d, C-2'ose’), 72.23 (d, C-S'ose’), 72.81 (d, C-3'ose"), 99.31 (d, C-1'ose’), 116.71 (d, Ar-C), 119.31 (s, Ph-Creso), 120.50 (8, Ar-Creso), 122.84 (d, Ar-C), 126.88 (d, Ph-C peta),

127.84 (d, Ar-C), 127.95 (d, Ph-Cpara), 129.99 (d, Ar-C), 134.61 (d, Ph-Corno), 142.01 (s, Ph-Cjpso), 143.78 (s, Ar-Cipso), 155.41 (s, Ar-Coou), 169.46 (s, C=0), 170.32 (s, C=0), 170.48 (s, C=O) ppm. ESI-HRMS: C72HesN4O20Na* ([M + Na]*): calculated 1329.4120, found 1329.4168. UV/vis (CHzCl2); Amax (log &/dm® mor” em”): 415 (5.41), 513 (3.79), 547 (3.56), 591 (3.26), 648 (3.36) nm. 18 Preparation of 5,10,15,20-tetrakis-[4-(2,3,4,6-tetraacetyl-B-D-glucosyl)pheny!]-porphyrin (Reference example) In a typical experiment, under argon atmosphere, Zn(Il)-5,10,15,20-(4-hydroxyphenyl)-porphyrin (50 mg, 62 pmol) was dissolved in 8 ml dry dichloromethane, 1 ml tetrahydrofuran and 1 ml acetonitrile. Then, 2,3,4,6- tetraacetyl-D-glucose trichloroacetimidate (0.8 g, 1.5 mmol) and BF3-Et2O (4.0 ul, 32 umol) were added. After stirring for 3 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue 23/63 PL 2

P 106691 LU101031 was dissolved in 10 mi tetrahydrofuran, and 0.8 ml of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (50 ml) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 ml). After drying with Na,SO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/methanol 99:1 as the eluent. The analytically pure product (93 mg, 69%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. AcO

OA OAc AcO 0 0 OAc AcO AcO OAc OAc AcO

Q Q OAc AcO. AcO OAc mp: 287 °C, 'H NMR (500 MHz, CDCk;): à = -2.83 (br s, 2 H, NH), 2.10 (s, 12 H, 4 x OAc), 2.11 (s, 12 H, 4 x OAc), 2.12 (s, 12 H, 4 x OAc), 2.21 (s, 12 H, 4 x OAc), 4.06 (ddd, J = 2.5, 5.4, 10.1 Hz, 4 H, H-5'ose’), 4.30 (dd, J = 2.5, 12.3 Hz, 4 H, H-Ga‘ose"), 4.42 (dd, J = 5.4, 12.3 Hz, 4 H, H-6g'ose"), 5.31 (dd, J = 9.6, 10.1 Hz, 4 H, H-4‘ose’), 5.45 (dd, J = 9.6, 9.6 Hz, 4 H, H-3‘ose’), 5.47 (d, J = 7.6 Hz, 4 H, H-1‘ose'), 5.49 (dd, J = 7.6, 9.6 Hz, 4 H, H-2'0ose’), 7.38 (d, J = 8.5 Hz, 8 H, 8 x Ar-Hrreta), 8.12 (d, J = 8.5 Hz, 8 H, 8 x Ar-Hortho). 8.85 (s, 8 H, B-H) ppm. °C NMR (126 MHz, CDCls): à = 20.73 (q, CHz), 20.77 (q, CHs), 20.86 (q, CHz), 20.90 (q, CHa),

62.18 (t, C-G'ose’), 68.48 (d, C-4'ose”), 71.43 (d, C-2'ose’), 72.39 (d, C-5'ose”), 72.93 (d, C-3'ose’), 99.25 (d, C-1‘ose’), 115.17 (d, Ar-Crmeta). 119.43 (s, Ar-Crmeso), 135.62 (d, Ar-Cortro), 137.21(s, Ar-Cipso), 156.74 (s, Ar- Cocu), 169.55 (s, C=0), 170.41 (s, C=O), 170.70 (s, C=0) ppm. ESI-HRMS: C4+o0H103N4040 * [M + H}:: calculated 1999.6149, found 1999.6078. UV/vis (CH2Cl2): Amax (log e/dm* mor” em”): 420 (5.20), 515 (3.89), 551 (3.66), 594 (3.46), 649 (3.39) nm. 24/63 Z fz

P 106691 LU101031

1.9 Preparation of 5,10,15,20-tetrakis-[3-(2,3,4,6-tetraacetyl-B-D-galactosyl)-phenyl]-porphyrin (Reference example) in a typical experiment, under argon atmosphere, Zn(ll)-5,10,15,20-(3-hydroxyphenyl)-porphyrin (50 mg, 62 pmol) was dissolved in 8 ml dry dichloromethane, 1 ml tetrahydrofuran and 1 mi acetonitrile. Then, 2,3,4,6- tetraacetyl-D-galactose trichloroacetimidate (0.8 g, 1.5 mmol) and BF3-Et,O (3.5 pl, 28 pmol) were added. After stirring for 3 hours, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 8 ml tetrahydrofuran, and 0.4 ml of hydrochloric acid (25%) were added. After stirring for 10 minutes, water (50 ml) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 ml). After drying with Na,SQO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/methanol 99:1 as the eluent. The analytically pure product (97 mg, 78%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol. This porphyrin is an atropisomer. OAcOAc oO te OAcPAc OAc ©

N AcO OAc @ ©) tr SL AcO OAcOAc ACC OAc La NM AcO © OAc mp: 225 °C, 'H NMR (500 MHz, (CD5),CO): 6 = -2.84 (br s, 2 H, NH), 0.97-1.04 (m, 12 H, 4 x OAc), 1.90-1.93 (m, 12 H, 4 x OAc), 2.06-2.09 (m, 12 H, 4 x OAc), 2.12 (s, 12 H, 4 x OAc), 4.00-4.09 (m, 8 H, H-6'0se’), 4.32-

4.37 (m, 4 H, H-5‘ose’), 5.24-5.28 (m, 4 H, H-3‘ose'), 5.37-5.40 (m, 4 H, H-4'ose"), 5.50-5.55 (m, 4 H, H- 2'ose’), 5.71-5.75 (m, 4 H, H-1‘ose’), 7.53-7.57 (m, 4 H, Ar-H), 7.75-7.80 (m, 4 H, Ar-H), 7.92-8.06 (m, 8 H, Ar-H), 8.93-8.97 (m, 8 H, B-H) ppm. ESI-HRMS: C4ooH403N4O40 “ ([M + HJ’): calculated 1999.6149, found

1999.6140. UVi/vis ((CH3)2CO): Amax (log &/dm® mol” cm”): 418 (5.54), 513 (4.22), 548 (3.74), 589 (3.69), 645 (3.38) nm. 25/63 y 2 / /7 “ Cs

P 106691 LU101031

1.10 Preparation of 5-[3-(2,3,4,6-tetraacetyl-B-D-glucosyl)phenyl]-10,15,20-tris-(pentafluoropheny!)- porphyrin In a typical experiment, under argon atmosphere, Zn(l[)-[5-(3-hydroxyphenyl)-10,15,20-tris- (pentafluorophenyl)-porphyrin (60 mg, 62 pmol) was dissolved in 10 ml dry dichloromethane. Then, 2,3,4,6- tetraacetyl-D-glucose trichloroacetimidate (132 mg, 268 umol) and BF3-Et;O (2.8 ul, 22 pmol) were added. After stirring for 20 minutes, the mixture was transferred to a separatory funnel. The organic layer was washed with water (2 x 50 ml) and the solvent was evaporated under reduced pressure. To remove the zinc, the residue was dissolved in 10 ml tetrahydrofuran, and 1.5 ml of hydrochloric acid (25%) were added; this step was repeated two more times. Then water (50 ml) and dichloromethane (75 ml) were added. The organic layer was separated and washed with water (2 x 50 mi). After drying with Na,SO,, the solvent was evaporated under reduced pressure. Further purification was achieved by flash chromatography, using dichloromethane/ethyl acetate 98:2 as the eluent. The analytically pure product (32 mg, 44%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol.

F F. © F OAc F F

O NÉ a RF OAc O va

F F F © F

F F

F mp: 190 °C, 'H NMR (700 MHz, CDCls): & = -2.84 (m, 2 H, NH), 1.41 (s, 3 H, OAc), 2.01 (s, 3 H, OAc), 2.06 (s, 3H, OAc), 2.13 (s, 3H, OAc), 3.83 (ddd, J =2.4, 5.6, 10.1 Hz, 1 H, H-S'ose”), 4.11 (dd, J = 2.4, 12.2 Hz, 1 H, H-6,'ose'), 4.18 (dd, J = 5.6, 12.2 Hz, 1 H, H-6g'0se’), 5.21 (dd, J = 9.2, 10.1 Hz, 1 H, H-4’ose’), 5.35 (dd, J =9.2, 9.2 Hz, H-3'ose"), 5.39 (d, J = 7.7 Hz, 1 H, H-1’ose’), 5.42 (dd, J = 7.7, 9.2 Hz, 1 H, H-2'0se’), 7.49-7.51 (m, 1 H, Ar-H), 7.73-7.76 (m, 1 H, Ar-H), 7.88-7.92 (m, 1 H, Ar-H), 7.95-7.98 (m, 1 H, Ar-H), 8.86-8.88 (m, 2 H, FH), 8.91-8.94 (m, 4 H, 8-H), 9.01-9.03 (m, 2 H, B-H) ppm. 3C NMR (176 MHz, CDCl): & = 19.87 (OCHa), 20.53 (OCH,3), 20.60 (OCHz), 20.72 (OCH), 61.94 (C-6'cse’), 68.26 (C-4'ose'), 71.23 (C-2'ose’),

72.19 (C-5'ose’), 72.70 (C-3'ose”), 99.07 (C-1’ose’), 102.07 (Arr-Creso), 103.11 (Arr-Cmeso), 115.60-115.94 (Are-Cipso), 117.21 (Ar-C), 122.12 (Ar-Creso), 122.81 (Ar-C), 128.05 (Ar-C), 129.90 (Ar-C), 136.77-136.94 (Arg- C), 138.21-138.32 (Are-C), 141.48-141.56 (Arr-C), 142.47 (Ar-Cipso), 142.86-142.95 (Arr-C), 145.76-145.96 (Arr-C), 147.12-147.35 (Are-C), 155.33 (Ar-Coou), 169.34 (C=O), 169.35 (C=O), 170.21 (C=0), 170.31 (C=0) ppm. °F NMR (471 MHz, CDCIs): & = -161.54 — -161.27 (m, 6 F, Ar-Freta), -151.57 — -151.42 (m, 3 F, Ar- Frara), -136.75 — -136.39 (m, 6 F, Ar-Fortno) ppm. ESI-HRMS: CseHzaF45N,O40Na * ([M + Na]'): calculated a ZZ

P 106691 LU101031

1253.1849, found 1253.1855. UV/vis (CHzCl2): Amax (log &/dm® mor! cm“): 414 (5.50), 508 (4.33), 585 (3.83) nm. Example 2 - Preparation of glycosylated deacetylated porphyrins

2.1 Preparation of 5-(4-a-D-mannosylphenyl)-10,15,20-triphenylporphyrin In a typical experiment, under argon atmosphere, 5-[4-(2,3,4,6-tetraacetyl-a-D-mannosy!)phenyl]-10,15,20- triphenylporphyrin (40 mg, 42 pmol) was dissolved in 5.0 ml dry tetrahydrofuran and 5.0 ml methanol. Then a solution of sodium methanolate in dry methanol (1.5 ml, 0.06 N) was added. After 2 h, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, using dichloromethane/methanol 9:1 as the eluent. The desired product (32 mg, 98%) was obtained as a violet crystalline solid. Ho HO O DO ©

HO

HO mp: 251 °C, 'H NMR (500 MHz, (CD3),S0): à = -2.91 (br s, 2 H, NH), 3.60-3.66 (m, 2 H, H-4'ose’, H-Ga'ose"),

3.68-3.72 (m, 1 H, H-5'0se’), 3.76-3.81 (m, 1 H, H-6p’ose’), 3.86-3.90 (m, 1 H, H-3‘ose'), 4.04-4.07 (m, 1H, H- 2'ose’), 4.63 (dd, J = 5.9, 5.9 Hz, 1 H, OH-6‘ose”), 4.87 (d, J = 5.6 Hz, 1 H, OH-3'0se’), 4.95 (d, J = 5.6 Hz, 1 H, OH-4'0se"), 5.17 (d, J = 4.6 Hz, 1 H, OH-2'cse’), 5.72 (d, J = 1.8 Hz, 1 H, H-1‘ose’), 7.53 (d, J = 8.7 Hz, 2 H, Ar-H, er), 7.80-7.85 (m, 9 H, 6 x Ph-Hreta, 3 X Ph-Hpara), 8.13 (d, J = 8.7 Hz, 2 H, Ar-Horiho), 8.20-8.23 (m, 6 H, Ph-Hornho), 8.82 (s, 6 H, BH), 8.88 (d, J = 4.6 Hz, 2 H, B-H) ppm. "°C NMR (126 MHz, (CD3)2SO): à = 61.79 (t, C-6'ose’), 67.44 (d, C-4’ose’), 70.84 (d, C-2'0se’), 71.42 (d, C-3’ose’), 75.89 (d, C-5'ose”), 100.00 (d, C- 1‘ose’), 115.91 (d, Ar-Creta), 120.43 (Ss, Ar-Cmeso), 120.52 (s, Ar-Creso), 127.56 (d, Ph-Creta), 128.64 (d, Ph- Cpara), 134.78 (d, Ph-Cortho), 135.28 (s, Ar-Cipso), 135.92 (Ar-Cortho), 141.78 (s, Ph-Cipso), 157.15 (s, Ar-Coman) ppm. ESI-HRMS: CsoH41N406 * (IM + HI"): calculated 793.3021, found 793.3067. UV/vis ((CH3)2S0): Amax (log e/dm* mol cm’) : 415 (5.38), 513 (4.10), 547 (3.77), 591 (4.01), 647 (3.40) nm.

P 106691 LU101031

2.2 Preparation of 5-(4-8-D-lactosylphenyl)-10,15,20-triphenylporphyrin In a typical experiment, under argon atmosphere, 5-[4-(2,3,4,6,2’,3 6 -heptaacetyl-B3-D-lactosyl)phenyl]- 10,15,20-triphenylporphyrin (37 mg, 30 pmol) was dissolved in 6.0 ml dry tetrahydrofuran and 6.0 ml methanol. Then a solution of sodium methanolate in dry methanol (2.0 mi, 0.06 N) was added. After 2 h, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, using dichloromethane/methanol 9:1 as the eluent. The desired product (28 mg, 98%) was obtained as a violet crystalline solid. oH OH OH Q 0 AA 50 ©

OH OH mp: > 300 °C, ‘H NMR (500 MHz, (CD3),S0): 6 = -2.93 (s, 2 H, NH), 2.98-3.03 (m, 2 H, Hose’), 3.48-3.79 (m, 9 H, ‘ose’), 3.85-3.89 (m, 1 H, ‘ose’), 4.35 (d, J = 7.2 Hz, 1 H, Hose’), 4.68 (d, J = 4.6 Hz, 1 H, OH'ose’),

4.82-4.88 (m, 2 H, OH'ose’), 4.93 (d, J = 1.6 Hz, 1 H, ‘ose’), 4.96 (d, J = 5.3 Hz, 1 H, ‘ose’), 5.20 (d, J = 4.0 Hz, 1 H, ‘ose’), 5.33 (d, J = 7.8 Hz, 1 H, H'ose’), 5.70 (d, J = 5.3 Hz, 1 H, OH‘ose”), 7.48 (d, J = 8.6 Hz, 2 H, Ar-Hrmeta), 7.81-7.86 (m, 9 H, 6 x Ph-Hppeta, 3 X Ph-Hpara), 8.13 (d, J = 8.6 Hz, 2 H, Ar-Horno), 8.20-8.23 (m, 6 H, Ph-Hortho), 8.81 (s, 6 H, B-H), 8.88 (d, J = 4.7 Hz, 2 H, B-H) ppm. ‘°C NMR (126 MHz, (CD5),SO): & = 60.62 (C'ose’), 60.83 (C'ose’), 68.61 (C'ose’), 71.33 (C'ose’), 73.77 (C'ose’), 73.95 (C'ose’), 75.45 (C'ose’), 75.70 (C'ose’), 76.13 (C'ose’), 80.61 (C'ose’), 104.34 (C'ose’), 115.12 (d, Ar-Creta), 120.42 (s, Ar-Creso), 120.45 (s, Ph-C eso), 120.54 (s, Ph-Cpeso), 127.59 (d, Ph-Creta), 128.67 (d, Ph-Cpara), 134.78 (d, Ph-Corñno), 135.81 (d, Ar- Cortho) 141.76 (s, Ph-Cipso). 157.91 (s, Ar-CoLac) ppm. ESI-HRMS: CseH5s1N4041 * ([M + HIM): calculated

955.3554, found 955.3554. UV/Vis ((CH3)2SO): Amax (log £/dm® mor” cm”) : 419 (4.79), 515 (3.54), 551 (3.27), 592 (3.10), 647 (3.05) nm.

2.3 Preparation of 5,15-bis-(3-B-D-glucosylphenyl)-10,20-dihexylporphyrin In a typical experiment, under argon atmosphere, 5,15-bis-[3-(2,3,4,6-tetraacetyl-B-D-glucosyl)-phenyl]-10,20- dihexylporphyrin (25 mg, 19 pmol) was dissolved in 5 ml methanol. Then a solution of sodium methanolate in dry methanol (1.0 mi, 0.02 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, using dichloromethane/methanol 8:2 as the eluent. The desired product (17 mg, 91%) was obtained as a violet crystalline solid. 28/63 GES ee

P 106691 LU101031

OH HO 0 To ee U) 0 OH SL dor

HO mp: > 300 °C, 'H NMR (500 MHz, CD;OD): & = 0.86-0.91 (br m, 6 H, 2 x CHz), 1.31-1.44 (br m, 8 H, 4 x CH), 1.66-1.74 (br m, 4 H, 2 x CH), 2.33-2.43 (br m, 4 H, 2 x CH), 3.40-3.89 (br m, 10 H, H’'ose’), 4.62-4.65 (br m, 2 H, Hose’), 4.85-4.93 (4 H, 2 x CH2), 5.22-5.25 (br m, 2 H, H’ose’), 7.57-7.61 (br m, 2 H, Ar-H), 7.66-

7.70 (br m, 2 H, Ar-H), 7.75-7.80 (br m, 2 H, Ar-H), 7.90-7.94 (br m, 2 H, Ar-H), 8.80-8.92 (br m, 4 H, 8-H),

9.34-9.46 (br m, 4 H, 8-H) ppm. ESI-HRMS: CseHe7N4012" ([M + HJ"): calculated 987.4750, found 987.4723. UV/vis ((CH3)2CO): Amax (log &/dm® mor" cr”) : 416 (5.18), 514 (3.86), 548 (3.58), 593 (3.30), 650 (3.40) nm.

2.4 Preparation of 5,15-bis-(4-B-D-glucosylphenyl)-10,20-dihexylporphyrin In a typical experiment, under argon atmosphere, 5,15-bis-[4-(2,3,4,6-tetraacetyl-B-D-glucosyl)-phenyl]-10,20- dihexylporphyrin (50 mg, 38 pmol) was dissolved in 9.0 ml dry tetrahydrofuran and 9.0 m! methanol. Then a solution of sodium methanolate in dry methanol (3.0 ml, 0.02 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, using dichloromethane/methanol 8:2 as the eluent. The desired product (36 mg, 97%) was obtained as a violet crystalline solid.

OH RO Ors ezsr™

HO HO OH

OH HO 29/63 AZ

P 106691 LU101031 mp: 226 °C, 'H NMR (500 MHz, (CD3)2SO): à = -2.92 (br s, 2 H, NH), 0.84 (t, J = 7.3 Hz, 6 H, 2 x CH), 1.24-

1.30 (m, 4 H, 4 x CH2), 1.35-1.41 (m, 4 H, 4 x CH), 1.69-1.75 (m, 4 H, 4 x CH2), 2.32-2.37 (m, 4 H, 4 x CH),

3.38-3.43 (m, 4 H, Hose’), 3.48-3.53 (m, 2 H, H'ose’), 3.55-3.61 (m, 2 H, H‘ose’), 3.79-3.83 (m, 2 H, H'ose’), 469-472 (m, 2 H, Hose’), 4.91-4.98 (m, 4 H, 2 x CH2), 5.25 (d, J = 7.4 Hz, 2 H, H-1'ose’), 7.46 (d, J = 8.6 Hz, 4 H, Ar-Hreta), 8.08 (d, J = 8.6 Hz, 4 H, Ar-Hortno), 8.82 (d, J = 4.8 Hz, 4 H, &-H), 9.64 (d, J = 4.8 Hz, 4 H, B-H) ppm. BC NMR (126 MHz, (CD3)2SO): à = 14.53 (q, CHa), 22.72 (t, CHy), 29.79 (t, CHz), 29.94 (t, CH2),

31.90 (t, CH»), 39.24 (t, CH,), 61.35 (t, C-6'0ose’), 70.36 (d, C'ose’), 74.00 (d, C'ose’), 77.26 (d, C'ose’), 77.80 (d, C'ose’), 101.12 (d, C-1'ose”), 114.97 (d, Ar-Creta), 118.78 (s, Ar-Creso), 120.49 (s, Alkyl-Creso), 135.68 (d, Ar-Corho), 157.90 (s, Ar-Cocu) ppm. ESI-HRMS: CseHe7N4042* (IM + HJ’): calculated 987.4750, found

987.4746. UV/vis ((CH3)2SO}: Amax (log g/ldm® mor cm”) : 420 (5.19), 519 (3.89), 554 (3.73), 597 (3.43), 654 (3.56) nm.

2.5 Preparation of 5,15-bis-(4-B-D-galactosylphenyl)-10,20-dihexylporphyrin In a typical experiment, under argon atmosphere, 5,15-bis-[4-(2,3,4,6-tetraacetyl-B-D-galactosyl)-phenyl]- 10,20-dihexylporphyrin (30 mg, 23 umol) was dissolved in 5.0 ml dry tetrahydrofuran and 5.0 mi methanol. Then a solution of sodium methanolate in dry methanol (1.8 mi, 0.02 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, using dichloromethane/methanol 8:2 as the eluent. The desired product (21 mg, 93%) was obtained as a violet crystalline solid. oH OH Lo ff Fou"

OH HO CH mp: 176 °C, '"H NMR (500 MHz, (CD3)2SO): à = -2.89 (br s, 2 H, NH), 0.86 (t, J = 7.5 Hz, 6 H, 2 x CHa), 1.28-

1.35 (m, 4 H, 2 x CH), 1.39-1.44 (m, 4 H, 2 x CH,), 1.71-1.78 (m, 4 H, 2 x CH), 2.35-2.42 (m, 4 H, 2 x CHy),

3.56-3.58 (m, 2 H, 2 x H-5‘ose’), 3.67-3.71 (m, 4 H, 2 x H-6‘ose’), 3.77-3.84 (m, 6 H, 2 x H-2'ose’, 2 x H- 3'ose’, 2 x H-4‘ose’), 4.64 (d, J = 4.7 Hz, 2 H, 2 x OH), 4.75-4.78 (m, 2 H, 2 x OH), 4.92-4.98 (m, 4 H, 2 x CH), 4.99 (d, J = 5.6 Hz, 2 H, 2 x OH), 5.20 (d, J = 7.8 Hz, 2 H, 2 x H-1'0se’), 5.40 (d, J = 5.2 Hz, 2 H, 2 x 30/63 FE pe

P 106691 LU101031 OH), 7.48 (d, J = 8.5 Hz, 4 H, Ar-Hpera), 8.09 (d, J = 8.5 Hz, 4 H, Ar-Hortno), 8.84 (d, J =4.4 Hz, 4 H, B-H), 9.65 (d, J = 4.4 Hz, 4 H, B-H) ppm. BC NMR (126 MHz, (CD3),SO): à = 14.52 (q, CHz), 22.71 (t, CH,), 29.94 (t, CHz), 30.98 (t, CH»), 31.89 (t, CHz), 34.91 (t, CHz), 39.22 (t, CH,), 61.12 (t, C-G'ose'), 68.86 (d, C'ose’), 71.08 (d, C'ose’), 74.01 (d, C-5'0se’), 76.31 (d, C'ose’), 101.83 (d, C-1'ose’), 115.03 (d, Ar-Creta), 118.81, 120.47,

135.67 (d, Ar-Corho). 158.02 (s, Ar-Coca) ppm. ESI-HRMS: CseHe7N4042 * (IM + HJ"): calculated 987.4750, found 987.4697. UV/vis ((CH3)2SO): Amax (log e/ldm® mol” em”): 424 (5.19), 519 (3.92), 555 (3.76), 597 (3.47), 654 (3.56) nm.

2.6 Preparation of 5,15-bis-(3-B-D-glucosylphenyl)-10,20-diphenylporphyrin In a typical experiment, under argon atmosphere, 5,15-bis-[3-(2,3,4,6-tetraacety!-B-D-glucosyl)-phenyl]-10,20- diphenylporphyrin (20 mg, 15 pmol) was dissolved in 4.0 ml dry tetrahydrofuran and 4.0 mi methanol. Then a solution of sodium methanolate in dry methanol (1.6 ml, 0.02 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography, using dichloromethane/methanol 8:2 as the eluent. The desired product (13 mg, 89%) was obtained as a violet crystalline solid. on ©“ oO

HO ne OO (4 Le Lo

HO OH

HO mp: > 300 °C, IH NMR (700 MHz, (CDs)2SO): à = -2.92 (br s, 2 H, NH), 3.20-3.24 (m, 2 H, H'ose’), 3.29-3.35 (m, 6 H, Hose’), 3.46-3.50 (m, 2 H, H-6,'0se’), 3.66-3.69(m, 2 H, H-6g'0se’), 4.54-4.56 (m, 2 H, OH'ose’),

4.98-5.00 (m, 2 H, OH'ose’), 5.09 (d, J = 4.9 Hz, 1 H, OH'ose’), 5.19-5.21 (m, 2 H, H-1‘ose’), 5.42 (d, J = 4.8 Hz, 1 H, OH'ose’), 7.52-7.55 (m, 2 H, Ar-H), 7.72-7.75 (m, 2 H, Ar-H), 7.83-7.89 (m, 8 H, 4 x Ph-Hpeta, 2 X Ph- Hpar, 2 x Ar-H), 7.89-7.91 (m, 2 H, Ar-H), 8.23-8.25 (m, 4 H, Ph-Homo), 8.84-8.93 (m, 8 H, BH) ppm. °C NMR (176 MHz, (CD3)2SO): & = 61.11 (t, C-G'ose’), 70.16 (d, C'ose’), 73.87 (d, C'ose’), 77.03 (d, C'ose’),

77.44 (d, C'ose’), 100.83-100.85 (d, C-1‘ose’), 116.28 (d, Ar-C), 120.06 (s, Ar-Crmeso), 120.46 (s, Ph-Crmeso),

122.88 (d, Ar-C), 127.50 (d, Ph-Crneta), 128.34 (d, Ar-C), 128.58 (d, Ph-Cpara), 128.93 (d, Ar-C), 134.66-134.72 (d, Ph-Cortho); 141.66 (s, Ph-C;pso}; 142.82 (s, Ar-Cipso), 156.35 (s, Ar-Cociu) ppm. ESI-HRMS: CseHs1N4042° (IM + HI’): calculated 971.3503, found 971.3530. UV/vis ((CHz)2SO): Amax (log e/dm* mor” em”): 416 (5.26), 513 (3.84), 547 (3.54), 590 (3.32), 649 (3.30) nm.

0 AA

P 106691 LU101031

2.7 Preparation of 5,10,15,20-tetrakis-(4-B-D-glucosyl)-porphyrin (Reference example) In a typical experiment, under argon atmosphere, 5,10,15,20-tetrakis-[4-(2,3,4,6-tetraacetyl-B-D- glucosyl)phenyl]-porphyrin (30 mg, 15 pmol) was dissolved in 6 ml dry tetrahydrofuran and 6 ml methanol. Then, a solution of sodium methanolate in dry methanol (0.6 mi, 0.12 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by RP48 flash chromatography, using methanol/water 9:1 as the eluent. The desired product (17 mg, 84%) was obtained as a violet crystalline solid.

HO OH

OH Ho] 0 0

OH HO HO OH

OH HO 0, 9” J oH

HO HO

OH mp: > 300 °C, 'H NMR (500 MHz, (CD5),S0): à = -2.91 (br s, 2 H, NH), 3.27-3.31 (m, 4 H, H'ose’), 3.40-3.45 (m, 8 H, Hose’), 3.49-3.54 (ddd, J = 1.9, 5.7, 9.5 Hz, 4 H, H-5'ose'), 3.56-3.62 (dd, J = 5.7, 11.8 Hz, 4 H, H- Bg'ose’), 3.79-3.83 (m, 4 H, H-B,'0s€’), 4.73 (t, J = 5.8 Hz, 4 H, OH'ose’), 5.12 (d, J = 5.4 Hz, 4 H, OH'ose’),

5.21 (d, J = 4.2 Hz, 4 H, OH'ose’), 5.23 (d, J = 7.2 Hz, 4 H, H-1‘ose”), 5.52 (d, J = 4.7 Hz, 4 H, OH'ose’), 7.48 (d, J= 8.5 Hz, 8 H, 8 x Ar-Hreta), 8.13 (d, J = 8.5 Hz, 8 H, 8 x Ar-Honno), 9.87 (s, 8 H, B-H) ppm. BC NMR (126 MHz, (CD;),S0): à = 61.36 (t, C-6'ose’), 70.35 (d, C'ose’), 74.01 (d, Cose’), 77.26 (d, C'ose’), 77.79 (d, C'ose’), 101.13 (d, C-1‘ose’), 115.11 (d, Ar-Creta), 120.18 (s, Ar-Creso), 135.21 (Ss, Ar-Cipso), 135.78 (d, Ar- Cortho), 158.06 (s, Ar-Cocu) ppm. ESI-HRMS: CesH74N4O24 “ [M + HJ: calculated 13274458, found 13274490. UV/vis ((CH3)2S0): Amex (log &/dm® mor” em“): 423 (5.67), 518 (4.62), 555 (4.51), 594 (4.33), 650 (4.31) nm.

P 106691 LU101031

2.8 Preparation of 5,10,15,20-tetrakis-(3-B-D-galactosyl)-porphyrin (Reference example) In a typical experiment, under argon atmosphere, 5,10,15,20-tetrakis-[3-(2,3,4,6-tetraacetyl-B-D- galactosy!)phenyl]-porphyrin (55 mg, 28 pmol) was dissolved in 2 ml dry tetrahydrofuran and 10 mi methanol. Then a solution of sodium methanolate in dry methanol (1.0 mi, 0.12 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by RP48 flash chromatography, using methanol/water 9:1 as the eluent. The desired product (30 mg, 82%) was obtained as a violet crystalline solid. This porphyrin is an atropisomer.

OH OH Ne

HO Oo te OH (OS ( su LT

HO

OH OH HO OH Ca MA HO ©

OH mp: 253 °C, 'H NMR (700 MHz, (CH3),S0): 6 = -2.95 (br s, 2 H, NH), 3.42-3.45 (m, 4 H, H'ose’), 3.48-3.52 (m, 4 H, Hose’), 3.55-3.59 (m, 8 H, H'ose’), 3.66-3.70 (m, 8 H, H'ose’), 4.59 (br s, 8 H, OH-‘ose’), 4.92 (br s, 4 H, OH-‘ose"), 5.12-5.18 (m, 4 H, H-1‘cse’), 5.30 (br s, 4 H, OH-ose"), 7.50-7.53 (m, 4 H, Ar), 7.71-7.75 (m, 4 H, Ar), 7.79-7.84 (m, 4 H, Ar), 7.87-7.90 (m, 4 H, Ar), 8.87-8.93 (m, 8 H, &H) ppm. ESI-HRMS: CesHzoN4024Na * ([M + Na]’): calculated 1349.4278, found 1349.4297. UV/vis ((CH3)2CO): Amax (log e/dm* mol! em”): 416 (5.09), 513 (3.67), 546 (3.45), 589 (3.36), 644 (3.30) nm.

2.9 Preparation of 5-(3-B-D-glucosylphenyl)-10,15,20-tris-(4-1'-thio-B-D-glucosyl-2,3,5,6-tetra- fluorophenyl)-porphyrin In a typical experiment, under argon atmosphere, 5-(4-B-D-glucosylphenyl)-10,15,20-tris-(pentafluorophenyl)- porphyrin (30 mg, 28 pmol) and 1-thio-B-D-glucose sodium sait (20 mg, 93 umol) were reacted in 4 ml dry DMF overnight at room temperature. Purification was achieved by column chromatography on silica using ethyl acetate/methanol (17:3) as the eluent. The analytically pure product (40 mg, 89%) was obtained as a violet crystalline solid. 33/63 ZZ LZ

P 106691 LU101031

HO OH

OH HO”/ oO s

F F OH F C F Q

A RF OH 0 (À SETZT

HO OH Fr H F. g F

F F Ss o” J oH

HO HO

OH mp: 243 °C, 'H NMR (700 MHz, CD;OD): à = -2.89 (s, 2 H, NH), 3.45-3.63 (m, 16 H, H-2"ose’, H-2'0se’, H- 3"ose’, H-3‘0ose’, H-4" ‘ose’, H-4‘ose’, H-5"0se’, H-5‘ose’), 3.72 (dd, J = 4.8, 11.9 Hz, 1 H, H-6g’ose’), 3.82 (dd, J = 6.2, 12.0 Hz, 2 H, H-65 ose’), 3.83 (dd, J = 6.2, 12.0 Hz, 1 H, H-65" ose’), 3.88 (dd, J = 1.9, 12.0 Hz, 1 H, H-Ga'ose"), 4.05 (dd, J = 2.2, 11.9 Hz, 2 H, H-6, ose’), 4.06 (dd, J = 2.2, 11.9 Hz, 1 H, H-6," ose’), 5.19-

5.23 (m, 3 H, H-1"0se’), 5.27 (d, J = 7.7 Hz, 1 H, H-1’ose’), 7.59-7.63 (m, 1 H, Ar-H), 7.64-7.68 (m, 1 H, Ar- H), 7.81-7.84 (m, 1 H, Ar-H), 8.02-8.05 (m, 1 H, Ar-H), 8.98-9.30 (m, 8 H, 8-H) ppm. *C NMR (176 MHz, (CDsOD): à = 61.04 (C-6'0se’), 61.70 (C-6"0se’), 69.96 (C'ose’), 70.32 (C-4" ose’), 73.63 (C'ose’), 74.59 (C- 2”0se’), 76.56 (C'ose’), 76.68 (C'ose’), 78.37 (C-3"ose’), 81.37 (C-5"ose’), 85.41 (C-1"0se’), 100.75 (C- 1’ose”), 102.86 (Are-Cmeso), 103.92 (Arr-Creso), 113.41-113.64 (Arr-Csou), 116.31 (Ar-C), 120.53-120.93 (Arg- Cipso), 122.41 (Ar-Creso), 122.83 (Ar-C), 127.59 (Ar-C), 128.78 (Ar-C), 142.15 (Ar-Cjpso), 145.58-145.67 (Arç- C), 146.43-146.56 (Are-C), 146.98-147.07 (Are-C), 147.87-147.95 (Arr-C), 156.20 (Ar-Cocu) ppm. PE NMR (471 MHz, CD4OD): à = -140.47 — -140.28 (m, 6 F, Ar-Frreta), -135.11 — -134.98 (m, 6 F, Ar-Forino) ppm. ESI- HRMS: CesHsaF42N4Na0O71S3 * ([M + Na]’): calculated 1613.2462, found 1613.2351. UV/vis (CH3OH); Amax (log e/dm“ mol” cm”): 411 (5.53), 506 (4.42), 580 (3.77), 636 (3.11) nm. 34/63 A 7 u

P 106691 LU101031

2.10 Preparation of 5-(3-B-D-glucosylphenyl)-10,15,20-tris-(4-1’-thio-B-D-galactosyl-2,3,5,6-tetra- fluorophenyl)-porphyrin In a typical experiment, under argon atmosphere, 5-(4-B-D-glucosylphenyl)-10,15,20-tris-(pentafluorophenyl)- porphyrin (30 mg, 28 jmol) and 1-thio-B-D-galactose sodium salt (20 mg, 93 pmol) were reacted in 4 ml dry DMF overnight at room temperature. Purification was achieved by column chromatography on silica using methanol/water (8:2) as the eluent. The analytically pure product (36 mg, 81%) was obtained as a violet crystalline solid. OH _ ou

OH H0”/ Oo s F. F OH F © F 0

A RF OH O DD HO

F F HO OH F. g F

F F S, 0° LOH

HO

HO HO mp: 267 °C. 'H NMR (700 MHz, CD;0D): 6 = -2.92 (s, 2 H, NH), 3.44-3.47 (m, 1 H, H-5'0se’), 3.48 (dd, J =

8.4, 9.8 Hz, 1 H, H-d'ose"), 3.54 (dd, J = 8.4, 9.0 Hz, 1 H, H-3'ose"), 3.61 (dd, J = 7.8, 9.0 Hz, 1 H, H-2'ose"),

3.69 (dd, J = 3.3, 9.3 Hz, 3 H, H-3"0se'), 3.72 (dd, J = 4.9, 12.0 Hz, 1 H, H-Gg'ose'), 3.75-3.78 (m, 3 H, H- 5"0se’), 3.85-3.93 (m, 10 H, 1 x H-6,‘ose', 3 x H-2" ose’, 3 x H-6,"0se', 3 x H-65 ose”), 4.03-4.05 (m, 3 H, H- 4”ose'), 5.12 (d, J = 9.5 Hz, 3 H, H-1"0se’), 5.26 (d, J = 7.8 Hz, 1 H, H-1'ose’), 7.58-7.62 (m, 1 H, Ar-H),

7.64-7.68 (m, 1 H, Ar-H), 7.78-7.81 (m, 1 H, Ar-H), 8.00-8.03 (m, 1 H, Ar-H), 8.93-9.32 (m, 8 H, &-H) ppm. °C NMR (176 MHz, (CD;0D): à = 61.00 (C-6'ose’), 61.33 (C-6 ose’), 69.22 (C-4"0se"), 69.93 (C-4’ose’), 71.43 (C-2"0se’), 73.60 (C-2'ose’), 74.94 (C-3"ose"), 76.52 (C-3'ose"), 76.63 (C-5'0se’), 79.91 (C-5" ose’), 86.28 (C- 1”ose"), 100.70 (C-1'ose’), 102.86 (Arr-Cmeso), 103.92 (Are-Creso), 113.28-113.52 (Arr-Cscai), 116.31 (Ar-C),

120.65-121.05 (Arr-C;pso), 122.39 (Ar-Crmeso), 122.82 (Ar-C), 127.62 (Ar-C), 128.80 (Ar-C), 142.11 (Ar-Cipso),

145.56-145.66 (Are-C), 146.63-146.71 (Are-C), 146.96-147.05 (Are-C), 148.01-148.10 (Arz-C), 156.14 (Ar- Cocu) ppm. ‘°F NMR (471 MHz, CDsOD): & = -140.52 — -140.32 (m, 6 F, Ar-Freta), -134.34 — -134.70 (m, 6 F, 35/63 Zr fry

P 106691 LU101031 Af-Fortho) ppm. ESI-HRMS: CesHsaF12N4NaO,1S3 * (IM + Na’): calculated 1613.2462, found 1613.2384. UV/vis (CH3OH): Amax (log e/dm® mor cm): 412 (5.57), 506 (4.29), 581 (3.81), 636 (2.98) nm. Example 3 - Preparation of glycosylated chlorins

3.1 Preparation of 5-(3-B-D-glucosylphenyl)-10,15,20-trihexyl-17,18-dihydroxy-17,18-chiorin In a typical experiment, osmium tetroxide (37 mg, 0.2 mmol) was added to a stirred solution of 5-[3-(2,3,4,6- tetraacetyl-B-D-glucosyl)phenyl]-10,15,20-trihexylporphyrin (120 mg, 0.12 mmol) in dichloromethane/pyridine 2:1 (6 ml). After stirring for 30 minutes at 0 °C and additional 8 hours at room temperature, a saturated solution of sodium bisulfite in water/methanol 1:1 (25 ml) was added and the mixture was stirred for 18 h. The reaction mixture was filtered through Celite and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography with dichloromethane/ethyl acetate 95:5 as eluent, followed by recrystallization from dichloromethane/methanol. The chlorin (30 mg, 24%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol, as a regioisomeric mixture. To a stirred solution of 5-[3-(2,3,4,6-tetraacetyl-B-D-glucosyl)phenyl]-10,15,20-trihexyl-17,18-dihydroxy-17,18- chlorin (25 mg, mmol) in dry tetrahydrofuran/methanol 1:1 (5 mi) under an argon atmosphere, a solution of sodium methanolate in dry methanol (1.0 ml, 0.02 N) was added. After 3 h, the solvent was evaporated under reduced pressure and the crude product was purified by RP flash chromatography, using methanol/water 9:1 as the eluent. The desired product (19 mg, 91%) was obtained after recrystallization from dichloromethane/aqueous methanol as a violet crystalline solid.

SH OH oO

HO a se N

AO mp: 135 °C, 'H NMR (500 MHz, (CD5),CO): 5 = -1.95 (s, 1 H, NH), -1.91 (s, 1 H, NH), 0.88-0.98 (m, 9 H, 3 x CHz), 1.32-1.55 (m, 12 H, 6 x CH), 1.73-1.85 (m, 6 H, 3 x CH), 2.21-2.44 (m, 6 H, 3 x CH2), 3.52-3.63 (m, 5 H), 3.67-3.74 (m, 1 H), 3.82-3.88 (m, 1 H), 4.18-4.20 (br s, 1 H), 4.30-4.32 (m, 1 H), 4.39-4.49 (m, 2 H, CH,),

4.61-4.67 (m, 2 H, CH,), 4.68-4.70 (m, 1 H), 4.74-4.80 (m, 2 H, CH), 5.25-5.28 (m, 3 H), 6.57-6.60 (m, 2 H, 36/63 FE de

P 106691 LU101031 B-H), 7.47-7.51 (m, 1 H, Ar-H), 7.63-7.67 (m, 1 H, Ar-H), 7.71-7.73 (m, 1 H, Ar-H), 7.79-7.82 (m, 1 H, Ar-H),

8.47-8.49 (m, 1 H, 8-H), 8.71-8.73 (m, 1 H, 6-H), 9.15-9.18 (m, 2 H, 8-H), 9.24-9.26 (m, 1 H, 8-H), 9.49-9.51 (m, 1 H, B-H) ppm. ESI-HRMS: CsoHe7N4Og “ [M + HI": calculated 851.5, found 851.5. UV/vis ((CH3)2CO): Amax (log e/dm® mor“ cm”): 406 (5.32), 428 (5.21), 525 (4.25), 551 (4.34), 596 (3.95), 649 (4.37) nm.

3.2 Preparation of 5,10,15-tris-(3-B-D-galactosylphenyl)-20-[3,5-bis-(trifluoromethyl)-phenyl]-17,18- dihydroxy-17,18-chlorin In a typical experiment, osmium tetroxide (100 mg, 0.39 mmol) was added to a stirred solution of 5,10,15-tris- [3-(2,3,4,6-tetraacetyl-B-D-galactosyl)phenyl]-20-[3,5-bis-(trifluoromethyl)phenyli]-porphyrin (300 mg, 0.17 mmol) in dichloromethane/pyridine 1:1 (26 ml). After stirring for 30 minutes at 0 °C and additional 2 hours at room temperature, a saturated solution of sodium bisulfite in water/methano! 1:1 (25 ml) was added and the mixture was stirred for 18 h. The reaction mixture was filtered through Celite and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography with dichloromethane/methanol 95:5 as eluent, followed by recrystallization from dichloromethane/aqueous methanol. The chlorin (129 mg, 42%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol, as a regioisomeric mixture. To a stirred solution of = 5,10,15-tris-[3-(2,3,4,6-tetraacetyl-B-D-galactosyl)phenyl]-20-[3,5-bis- (trifluoromethyl)phenyl]-17,18-dihydroxy-17,18-chlorin (46 mg, 25 umol) in dry tetrahydrofuran/methanol 1:1 (10 ml) under an argon atmosphere, a solution of sodium methanolate in dry methanol (1.0 mi, 0.1 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by RP45 flash chromatography, using methanol/water 85:15 as the eluent. The desired product (33 mg, 99%) was obtained as a violet crystalline solid after washing with dichloromethane. This chlorin is an atropisomer. oH PH Oo

O

SA on) oH OH OH 0

OH SA CFs oO 4 CF;

DO

O HO 9

OH 37/63 AZ 2

P 106691 LU101031 mp: > 300 °C, 'H NMR (500 MHz, CD;OD): à = 3.54-3.88 (m, 18 H, H'ose"), 5.02-5.12 (3 H, H'ose'), 6.13-6.36 (m, 2 H, ß-H), 7.39-8.79 (m, 21 H, 6 x ß-H, 15 Ar-H) ppm. ESI-HRMS: CesHeoFeN,Oz0Na © ([M + Nal’): calculated 1341.3597, found 1341.3594. UV/vis ((CHz)2CO): Amax (log e/dm® mol! cm”): 407 (4.51), 515 (3.53), 541 (3.49), 594 (3.18), 646 (3.78) nm.

3.3 Preparation of 5,10,15-tris-(3-B-D-lactosylphenyl)-20-[3,5-bis-(trifluoromethyl)-phenyl}17,18- dihydroxy-17,18-chlorin In a typical experiment, osmium tetroxide (100 mg, 0.39 mmol) was added to a stirred solution of 5,10, 15-tris- [3-(2,3,4,6,2',3' 6'-heptaacetyl-B-D-lactosyl)-phenyi]-20-[3,5-bis-(trifluoro-methyl)phenyl]-porphyrin (350 mg,

0.13 mmol) in dichloromethane/pyridine 1:1 (15 ml). After stirring for 30 minutes at 0 °C and additional 2 hours at room temperature, a saturated solution of sodium bisulfite in water/methanol 1:1 (25 ml) was added and the mixture was stirred for 18 h. The reaction mixture was filtered through Celite and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by flash chromatography with dichloromethane/methanol 95:5 as eluent, followed by recrystallization from dichloromethane/aqueous methanol. The chlorin (39 mg, 8%) was obtained as a violet crystalline solid after recrystallization from dichloromethane/aqueous methanol, as a regioisomeric mixture. To a stirred solution of 5,10,15-tris-[3-(2,3,4,6,2',3',6'-heptaacetyl-D-lactosyl)phenyl]-20-[3,5-bis- (trifluoromethyl)phenyl]-17,18-dihydroxy-17,18-chlorin (32 mg, 12 pmol) in dry tetrahydrofuran/methanol 1:1 (10 ml) under an argon atmosphere, a solution of sodium methanolate in dry methanol (1.5 ml, 0.1 N) was added. After 4 h, the solvent was evaporated under reduced pressure and the crude product was purified by RP; flash chromatography, using methanol/water 85:15 as the eluent. The desired product (21 mg, 98%) was obtained as a violet crystalline solid after washing with dichloromethane. This chiorin is an atropisomer. oH OH OH

A

OH OH OH OH OH © HO A OH CF,

OH OH

D U CF3 oH OH OH a, TI

OH OH 38/63 ZZ L

TA

P 106691 LU101031 mp: > 300 °C, 'H NMR (500 MHz, CD,0D): & = 3.43-3.84 (m, 36 H, Hose"), 4.31- 4.38 (m, 3 H, Hose’), 5.17-

5.25 (m, 3 H, H'ose'"), 6.13-6.32 (m, 2 H, 3-H), 7.39-8.80 (m, 21 H, 6 x 8-H, 1 Ar-H) ppm. ESI-HRMS: CazHooFsN4OssNa * ([M + Na]*): calculated 1827.5182, found 1827.5282. UV/vis (CH3CH2OH): Amax (log &/dm* mol” cm™): 415 (4.92), 514 (3.86), 541 (3.83), 594 (3.49), 646 (4.12) nm.

Example 4 - Cell tests of selected compounds in the HT 29 and other cell lines The photosensitizing activity was determined in the following cell lines: - HT29 (human colon adenocarcinoma cell line) - L929 (mouse fibroblast cell line) - A431 (human epidermoid carcinoma cell line) - A253 (submaxillary salivary gland, epidermoid cell line) - CAL-27 (human tongue squamous cell carcinoma cell line).

The cell lines were grown in DMEM (PAA Laboratories GmbH) supplemented with 10 % heat-inactivated fetal calf serum (FCS, PAA Laboratories GmbH), 1 % penicillin (10000 IU) and streptomycin (10000 ug/ml, PAA Laboratories GmbH). Cells were kept as a monolayer culture in a humidified incubator (5 % CO, in air at 37 °C).

A photosensitizer stock solution (2 mM) was performed in DMSO and was kept in the dark at 4 °C.

Further dilution was performed in DMEM medium without phenol red supplemented with 10 % FCS to reach a final photosensitizer concentration of 2 or 10 uM, respectively.

2 - 10* cells/ml were seeded in micro plates (2 - 10° cells/well). Cells were incubated with fresh medium (DMEM without phenol red) containing 10 % FCS with 2 or 10 uM of the photosensitizer for 24 h before light exposure. Before photosensitization, cells were washed, cell culture medium was exchanged with DMEM without pheno! red and 10 % FCS, then irradiated at room temperature with a 652 nm diode laser (Ceralas PDT 652, biolitec AG) at a fixed fluence rate of 100 mW/cm? (50 Jicm?). Following irradiation, cells were incubated in a humidified incubator (5 % CO; in air at 37 °C) for 24 h until cell viability assay.

The cell viability was assessed by the XTT assay. 500 mg XTT (sodium 3’-[phenylaminocarbonyl)-3,4- tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid, Applichem GmbH) is dissolved in 500 ml PBS- Buffer (without Ca** and Mg®*) and sterile filtered. Solution was stored in the dark at -20 °C until use. A sterile solution containing PMS (N-methyl dibenzopyrazine methyl sulfate, Applichem GmbH) was needed as an activation reagent for the XTT. 0.383 mg PMS was dissolved in 1 ml PBS-Buffer. The solution should be stored frozen and should not be exposed to light. The XTT reagent solution was thawed in a 37 °C water bath and the activation solution (PMS) was added immediately prior to use. To prepare a reaction solution sufficient for one micro plate (96 wells), 0.1 ml activation solution (PMS) was given to 5 ml XTT reagent. The medium in the micro plate was exchanged with RPMI without phenol red 39/63 A Ad

P 106691 LU101031 and 10 % FCS (100 ul) prior adding 50 ul XTT reaction solution per well. The micro plate was incubated for 2-3 hours at 37 °C and 5 % CO, until an orange dye is to be formed. The micro plate has been shaken gently to evenly distribute the dye in the wells. The absorbance of the samples was measured with a spectrophotometer (Infinite 200, Tecan Group Ltd.) at a wavelength of 490 nm. In order to measure reference absorbance (to measure non-specific readings) a wavelength of 630-690 nm was used. The results of Examples 4.1 to 4.5, which are shown in Figures 1 to 5, illustrate the photodynamic activity (“DT” means dark toxicity and “Laser” means photo toxicity) of photosensitizers having a substitution pattern according to the present invention. Specifically the photosensitizers according to the invention exhibit a strong photodynamic activity even in the HT29 cell line, which is known to be very resistant against cell-toxic agents and PDT as well. The results of Examples 4.6 to 4.9, which are shown in Figures 6 to 9, are included to illustrate, that photosensitizers which do not have a substitution pattern as referred to in the present invention exhibit a less promising photodynamic activity in the cell experiments, in particular with respect to cell line HT29.

- F6 hf

Claims (17)

P 106691 LU101031 Claims

1. À tetrapyrrolic compound having a structure of Formula 1, 2, or 3: O-R O=p1 n° Ry TR B Sy B x ; Sa N= ; Si N= A 8 R rR? R n° | \ No HN 1 S FNS N CM

AD 1 Rr? 2 R' 3 oO o—R' wherein B is

H H i PA ; OH ; €, SSH Hz A OH ’ H A H , H C m 7 or on O-R' is a substituent in the meta or para position of the phenyl ring, R'is a glyco-substituent derived from a mono-, di-, or trisaccharide group, and each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, phenyl pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyi, 4-(1'-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH2CH20).CHz with n = 1-30, wherein (a) in Formula 1 or 2, if Bis vo Eds

P 106691 LU101031 , H

SSH N= O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched alkyl group with 5 to 8 carbon atoms, a linear or branched fluoroalkyl group with 3 to 8 carbon atoms, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6-tetrafluoro- phenyl, 4-(1’-thio-8-D-galactosyl)-2,3,5,6-tetrafluorophenyl, meta- or para- hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO- phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30, (b) in Formula 1 or 2, if Bis , H

INH N= O-R* is a substituent in the para position of the phenyl ring and R! is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1"-thio-B-D- glucosyl)-2,3,5,6-tetrafluorophenyl, 4-(1’-thio-B-D-galactosyl)-2,3,5,6- tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para- carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30, (c) in Formula 1 or 2, if O-R" is a substituent in the meta position of the phenyl ring and R' is glucosyl and R? is n-hexyl, phenyl or 3,5- bis(trifluoromethyl)phenyl, then B is 42/63

EG

P 106691 LU101031

H ooo ; OH „OH, / H OH 2 OH ’ H ‘ H J H N= N= N= ” 7 or 7 , (d) in Formula 1 or 2, if O-R' is a substituent in the meta position of the phenyl ring and R' is galactosyl and R? is phenyl, then B is

H H H ; OH ; on, + H OH A OH . H . H K H N= N= N= ” 5 or 7 ,Ç (e) in Formula 3, if Bis ; H

SSH N== O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R?is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1’-thio-B-D-glucosyl)- 2,3,5,6-tetrafluorophenyl, 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluoro- phenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH2CH,0),CH3 with n = 1-30, (ff) in Formula 3, if B is 43/63 FE

P 106691 LU101031 ; H ; H " H ’ H N= O-R' is a substituent in the meta position of the phenyl ring and R’ is glucosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1-thio-B-D-glucosyl)- 2,3,5,6-tetrafluorophenyl, 4-(1-thio-B-D-galactosyl)-2,3,5,6-tetrafluoro- phenyl, meta- or para-hydroxyphenyl, meta- or para-carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH2CH20),CHz with n = 1-30, and (g) in Formula 3, if B is , H

SNH N= O-R' is a substituent in the para position of the phenyl ring and R' is galactosyl, then each R° is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D- glucosy!)-2,3,5,6-tetrafluorophenyl, 4-(1’-thio-B-D-galactosyl)-2,3,5,6- tetrafluorophenyl, meta- or para-hydroxyphenyl, meta- or para- carboxyphenyl, and meta- or para-YO-phenyl with Y being a polyethyleneglycol-residue with (CH,CH,0),CH; with n = 1-30.

2. The tetrapyrrolic compound according to claim 1, wherein (a) in Formula 1 or 2, if B is 0 ZZ CL

P 106691 LU101031 ; H

A SCH N= O-R' is a substituent in the para position of the pheny! ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched alkyl group with 5 to 8 carbon atoms, a linear or branched fluoroalkyl group with 3 to 8 carbon atoms, 3,5-bis(trifluoromethyl)phenyl, 4-(1-thio-B-D-glucosyl)-2,3,5,6- tetrafluorophenyl, and 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, (b) in Formula 1 or 2, if B is , H

OSTNH N= O-R' is a substituent in the para position of the phenyl ring and R' is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5- bis(trifluoromethy!)phenyl, 4-(1-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl, and 4- (1-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, (e) in Formula 3, if B is , H

SN H N== O-R' is a substituent in the para position of the phenyl ring and R' is glucosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl, and 4- (1’-thio-B-D-galactosy!)-2,3,5,6-tetrafluorophenyl, 45/63 ZZ

P 106691 LU101031 (f) in Formula 3, if B is , H ; H ni H ‘ H N= O-R' is a substituent in the meta position of the phenyl ring and R'is glucosyl, then each R? is independently selected from the group consisting of a linear or branched {fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyl, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl, and 4- (1’-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl, and (g) in Formula 3, if B is ; H

SSH N= O-R' is a substituent in the para position of the phenyl ring and R'is galactosyl, then each R? is independently selected from the group consisting of a linear or branched (fluoro-)alkyl group with 3 to 8 carbon atoms, pentafluorophenyi, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosyl)-2,3,5,6-tetrafluorophenyl, 4-(1"- thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl.

3. The tetrapyrrolic compound according to claim 1 or 2, wherein R' is a glycosyl group of a mono- or disaccharide, wherein the mono- or disaccharide is preferably selected from the group consisting of glucose, galactose, mannose, ribose, fructose, rhamnose, lactose, partially deoxygenated derivatives thereof, aminosugars, such as glucosamines or galactosamines, neuraminic acids and combinations thereof.

4. The tetrapyrrolic compound according to any of the previous claims, wherein R is mannosyl or lactosyl and R? is a linear or branched (fluoro-)alky! group with 3 to 8 carbon 46/63 ZC hd

P 106691 LU101031 atoms, phenyl, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosy!)- 2,3,5,6-tetrafluorophenyl or 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl.

5. The tetrapyrrolic compound according to claim 4, wherein B is ; H

SNH N= O-R' is a substituent in the para position of the phenyl ring and R? is phenyl.

6. The tetrapyrrolic compound according to any one of claims 1 to 3, wherein in Formula 1 or 2 O-R' is a substituent in the meta position of the phenyl ring, R' is glucosyl and each R? is a linear or branched fluoroalkyl group with 3 to 8 carbon atoms, 3,5- bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D-glucosy!)-2,3,5,6-tetrafluorophenyl or 4-(1’-thio- B-D-galactosyl)-2,3,5,6-tetrafluorophenyl.

7. The tetrapyrrolic compound according to any one of claims 1 to 3, wherein in Formula 3 B is ; H

SSH N== R'is glucosyl or galactosyl and each R? is a linear or branched (fluoro-)alkyl group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1'-thio-B-D- glucosyl)-2,3,5,6-tetrafluorophenyl or 4-(1’-thio-B-D-galactosyl)-2,3,5,6-tetrafluorophenyl.

8. The tetrapyrrolic compound according to any one of claims 1 to 3, wherein in Formula 1 or2 Bis 47/63 Zs

P 106691 LU101031

H / OH

A OH ° H N — R'is glucosyl or galactosyl and each R? is a linear or branched (fluoro-)alky! group with 5 to 8 carbon atoms, pentafluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 4-(1’-thio-B-D- glucosyl)-2,3,5,6-tetrafiuoropheny! or 4-(1'-thio-B-D-galactosyl)-2,3,5,6-tetrafiuorophenyl.

9. The tetrapyrrolic compound according to claim 8, wherein R'is glucosyl and R? is a linear or branched alkyl group with 5 to 8 carbon atoms.

10. The tetrapyrrolic compound according to any one of claims 1 to 3 which compound is selected from the group consisting of

HO HO O 0) ©

HO

HO oH OH OH

O TAO v

HO HO

OH OH 48/63 A

P 106691 LU101031 FC C CF3 OH CF3

OT FC

AN OH CF3 Fol Ç CFs

F

F F

OH F CC F

PRY A F F

HO OH

F (5 rs)

FF

ES

F F XX, F ,

HO

OH

OH HO Oo

S F ® F

OH F F oO eA a RF

OH

CS ZZ

HO OH F + HO F @ F

F F Ss

Q OH

HO

HO OH , 49/63 GET

P 106691 LU101031

OH OH

OH HO Oo Ss

F F

O HA a RF

OH s 0 OH

O ZA F + HO CH F 0 F

F F Ss

O OH

HO HO— 0 ,

OH

O

HO HY ) > o OH ALL Lo

HO

OH 0, oO OH oxo) COLD

OH HO 50/63 ZZ

P 106691 LU101031 ox PH VO Ors zr

HO HO

OH HO OH

N J oO

HO Ao © v > 0 OH

HO OH

OS HO and

OH OH 0

HO

TO

11. The tetrapyrrolic compound according to claim 10 selected from the group consisting of 51/63 €,

P 106691 LU101031

OH PH OH 0

Q

O AN AN @ U)

OH OH

OH A0 IRs

HO HO OH

OH HO O4 Orr

HO HO OH ho CH , and 52/63 A L EL

P 106691 LU101031

OH OH 0

HO

AN OH “0

12. The tetrapyrrolic compound according to any one of claims 1 to 11, wherein O-R' is a glycosidic bond.

13. A pharmaceutical composition comprising a tetrapyrrolic compound according to any of the previous claims, wherein the pharmaceutical composition is preferably a liposomal formulation.

14. The pharmaceutical composition according to claim 13 further comprising PLGA particles, HSA particles, cyclodextrines and/or polymer particles.

15. The pharmaceutical composition according to claim 13 or claim 14, wherein the tetrapyrrolic compound is conjugated to a targeting agent, wherein the targeting agent is preferably selected from the group consisting of an antibody or fragment thereof.

16. A tetrapyrrolic compound according to any of claims 1 to 12 for use in photodynamic therapy, in particular photodynamic therapy of tumors, dermatological disorders, ophthalmological disorders, urological disorders, arthritis and other inflammatory diseases.

17. A tetrapyrrolic compound according to any of claims 1 to 12 for use in diagnosis.

53/63 FA A LC