WO2002000662B1 - Improvements in and relating to chromophores - Google Patents

Abstract

The present invention relates to novel porphyrin and porphyrin-based chromophores and sets of porphyrin and porphyrin-based chromophores, which may be particularly useful in a range of photodynamic applications, including photochemotherapy and fluorescence analysis and imaging. In particular, the present invention provides new and useful porphyrin, chlorin and bacteriochlorin chromophores; methods for the production of such chromophores; and methods for the use of such chromophores in analysis and in medicine.

Claims

AMENDED CLAIMS

[received by the International Bureau on 17 January 2002 (17.01.02); original claims 1, 3, 4, 5, 6, 7 and 8 amended; remaining claims unchanged (8 pages)]

A porphyrin chromophore of formula (I) below:

or a chlorin chromophore of any of formulas (II), (III), (IV), or (V) below:

OD (HI)

101

or a bacteπochloπn chromophore of any of formulas (VI) and (VII) below:

(VI) (VII)

wherein Rj is an aryl moiety which is linked to a conjugating group Z which is capable of conjugating the chromophore to a polypeptide molecule for delivering said chromophore to a specific biological target in vitro or in vivo,

R₂ is a hydrophihc aryl moiety,

R₃ is H or a hydrophihc aryl or hydrophihc non-aromatic moiety, and each of Xi, X₂, X₃ and X is independently selected from H. OH, halogen, Ci ₃ alkyl and OC₁.₃ alkyl, or Xi and X₂ and/or X₃ and X together form a bridging moiety selected from O, CH₂, CH C1_..₃ alkyl, or C(d ₃ alkyl)₂, such that X, and X₂ and/or X₃ and X with the adjacent C-C bond form an epoxide or cyclopropanyl structure, wherein one or both of said R2 and said R₃ compπses either a phenyl πng which is substituted one or more times, preferably at least two times, by one or more hydrophihc substituents which serve to increase the hydrophihcity of said R and/or said R₃, or a heteroaryl πng, such as a quartemsed pyπdyl (pyπdiniumyl) πng, which πng is

102 optionally substituted one or more times, preferably at least two times, by one or more hydrophihc substituents which serve to increase the hydrophihcity of said R2 and/or said

said one or more hydrophihc substituents being independently selected from hydroxy, alkoxy such as methoxy or ethoxy, C2-C15 polyethylene glycol, quartenised pyπdyl (pyπdtniumyl) such as N-methylpyπdiniumyl, mono-, di- or poly-sacchaπde; C_{\ 6}alkylsulfonate; a phosphonium group R₄P(R5)( 6)( 7), wherein R is a single bond or Ci ₆ alkyl, and each of R₅, R₆ and R₇ is independently selected from hydrogen, an aryl πng such as a phenyl πng, a heteroaryl πng such as a pyπdyl πng, and a Cι_₆ alkyl chain, which aryl πng, heteroaryl πng or C| ₆ alkyl chain is unsubstituted or is substituted one or more times by hydroxy, C| ₆ alkyl or alkoxy, aryl, oxo, halogen, nitro, amino or cyano; or a phosphate or phosphonate group R₈OP(O)(OR₉)(OR,₀) or R₈P(O)(OR₉)(OR₁₀) respectively, wherein R is a single bond or C_{\ 6} alkyl, and each of R₉ and Rio is independently selected from hydrogen and C. ₆ alkyl, wherein each of said Ri, R₂ and R₃ is optionally further substituted one or more times by -OH, -CN, -NO₂, halogen, -T or -OT, where T is a C1-C1₅ alkyl, cycloalkyl or aryl group or a hydroxylated, halogenated, sulphated, sulphonated or aminated deπvative thereof or a carboxyhc acid, ester, ether, polyether, amide, aldehyde or ketone deπvative thereof

2 A chromophore as claimed in claim 1 , wherein said aryl moiety Ri compπses a phenyl nng, which phenyl πng is either linked by a single bond to the macrocyc c core of said chromophore or is linked thereto by a C| branched or linear alkyl chain

3 A chromophore as claimed in any of claims 1-3, wherein R₃ is H or is a hydrophihc alkyl moiety, such as a ₆ alkyl chain which is substituted one or more times by one or more hydrophihc substituents such as hydroxy or C_{2 15} polyethylene glycol.

4 A chromophore as claimed in any of claims 1-3, wherein R₃ compπses a hydrophihc aryl moiety which is the same as said hydrophihc aryl moiety R₂

103 5 A chromophore as claimed in any preceding claim, wherein one or both of said R₂ and said R₃ is or are independently selected from m,m-(dιhydroxy)phenyl

or a PEGylated deπvative thereof; m,m,p-(tπhydroxy)phenyl

or a PEGylated deπvative thereof; o,p,o-(tπhydroxy)phenyl

or a PEGylated deπvative thereof; m- or p-((Cι ₆)aIkyltriphenylphosphonιum)phenyl such as p-(methyltπphenylphosphonιum)phenyl

m- or p-(Cι_₆alkylphosphono-dι-alkoxy)phenyl such as p-methylphosphono-di- ethoxy)phenyl

Λ

EtO OEt m- or p-(Cι-₆alkylphosphonato-dι-alkoxy)phenyl such as p-methylphosphonato- dι-ethoxy)phenyl

104

m- or p-(N-methyl-pyridιnιumyl)phenyl

meta- or para- sugar-substituted phenyl such as pentose-, hexose- or disaccharide - substituted phenyl

and a quartenised pyπdyl (pyπdiniumyl) group such as a p-N-(C). ₆alkyl)pyridiniumyl group or m-N-(C|.₆alkyl)pyndιnιumyl group such as m-N- methylpyridiniumyl

or p-N-methylpyridiniumyl

and a zwitterionic group, such as p-N-(Cι„₆alkylsulfonate)pyridiniumyl or m-N- (Cι.₆alkylsulfonate)pyridiniumyl; in particular, p-N-(propylsulfonate)pyridiniumyl

105

or m-N-(propylsulfonate)pyπdιnιumyl

6 A chromophore as claimed in claim 1, characteπsed in that said R₃ is H and said

R₂ is selected from:

where Wi is Cι_₆ alkyl or a hydrophihc substituent selected from hydroxy; alkoxy such as methoxy or ethoxy; C₂-C₁₅ polyethylene glycol, quartenised pyπdyl (pyπdimumyl) such as N-methylpyndimumyl; mono-, di- or poly-sacchaπde; ₆alkylsulfonate; a phosphomum group R₄P(R₅)(R₆)(R₇), wherein R₄ is a single bond or Cι_-6 alkyl, and each of R₅, R₆ and R₇ is independently selected from hydrogen, an aryl πng such as a phenyl πng, a heteroaryl πng such as a pyπdyl πng, and a Ci β alkyl chain, which aryl πng, heteroaryl πng or C).₆ alkyl chain is unsubstituted or is substituted one or more times by hydroxy, Cι_₆ alkyl or alkoxy, aryl, oxo, halogen, nitro, amino or cyano; or a phosphate or phosphonate group R₈OP(O)(OR₉)(ORι₀) or R₈P(O)(OR₉)(ORι₀) respectively, wherein R₈ is a single bond or Cι_-6 alkyl. and each of R₉ and Rio is independently selected from hydrogen and Cι_₆ alkyl, and

where W₂ is hydrogen, Ci ₆ alkyl, a heterocyc c group or an aromatic group

106 7 A chromophore as claimed in claim 1, characteπsed in that said R₂ and said R₃ are the same one of

wherein W₃ is hydrogen or a hydrophihc substituent selected fiom hydroxy; alkoxy such as methoxy or ethoxy, C₂-C₁₅ polyethylene glycol, quartenised pyπdyl (pyπdiniumyl) such as N-methylpyπdiniumyl, mono-, di- or poly-sacchaπde, Ci ₆alkylsulfonate, a phosphonium group R₄P(R₅)(R₆)(R7), wherein R₄ is a single bond or ₆ alkyl, and each of R₅, R₆ and R₇ is independently selected from hydrogen, an aryl πng such as a phenyl πng, a heteroaryl πng such as a pyπdyl πng, and a C_{\ 6} alkyl chain, which aryl πng, heteroaryl πng or Ci alkyl chain is unsubstituted or is substituted one or more times by hydroxy, Ci ₆ alkyl or alkoxy, aryl, oxo, halogen, nitro, amino or cyano, or a phosphate or phosphonate group R₈OP(O)(OR₉)(OR₁₀) or R₈P(O)(OR₉)(OR₁₀) respectively, wherein R₈ is a single bond or C| ₆ alkyl, and each of R₉ and Rio is independently selected from hydrogen and Ci ₆ alkyl, or

wherein W₄ is selected from OH, ONa, and O(Cι ₆ alkyl)

8 A chromophore as claimed in claim 1, wherein said R₃ is

OH

.OH

107 and said R₂ is a group

wherein W₅ is a hydrophihc substituent selected from hydroxy; alkoxy such as methoxy or ethoxy; C₂-C₁₅ polyethylene glycol; quartenised pyπdyl (pyπdimumyl) such as N- methylpyπdimumyl; mono-, di- or poly-sacchaπde; Cι.₆alkylsulfonate; a phosphonium group R P(R₅)(R₆)(R₇), wherein R is a single bond or Cι.₆ alkyl, and each of R₅, R₆ and R₇ is independently selected from hydrogen, an aryl πng such as a phenyl πng, a heteroaryl πng such as a pyπdyl πng, and a C_{\ 6} alkyl chain, which aryl πng, heteroaryl πng or Ci ₆ alkyl chain is unsubstituted or is substituted one or more times by hydroxy, Cι-₆ alkyl or alkoxy, aryl, oxo, halogen, nitro, amino or cyano, or a phosphate or phosphonate group R₈OP(O)(OR₉)(OR,₀) or R₈P(O)(OR₉)(OR,₀) respectively, wherein R₈ is a single bond or Ci ₆ alkyl, and each of R₉ and R₎₀ is independently selected from hydrogen and Cι_-6 alkyl; and X is C or N.

9 A 5,15-dιphenylporphyπn, 5,15-dιphenylchloπn or 5,15-dιphenylbacteπochloπn chromophore, wherein each of the ortho-, meta-, and/or para- positions of each of the 5- and 15- phenyl groups is substituted by a substituent P₁-P₅ and QrQs respectively which is independently H or an inert substituent which in combination with the other substituents Pι-P₅ and Q Qs does not substantially impair the fluorescent properties of the chromophore; and the chromophore further compπses a conjugating group Z which is capable of conjugating the chromophore to a polypeptide molecule for dehveπng said chromophore to a specific biological target in vitro or in vivo

10 A chromophore as claimed in claim 9, which is selected from the following compounds:

108 STATEMENT UNDER ARTICLE 19(1)

The claims of the above PCT patent application have been amended in order to define the subject matter of this application more clearly over the prior art.

Basis for the amended claims may be found as follows in the application as filed:

Claim 1 is based on original claims 1 and 3-5

Claim 2 is unamended

Claims 3 and 4 correspond to original claims 7 and 8

Claim 5 corresponds to original claim 6

Claim 6 is based on pages 10-11 of the description as filed

Claim 7 is based on pages 12-13 of the description as filed

Claim 8 is based on page 18 of the description as filed

Claims 9-43 are unamended