In-vivo diagnostic method by means of near infrared radiation
View Patent ↗This invention relates to an in-vivo diagnostic method based on near infrared radiation (NIR radiation) that uses water-soluble dyes and their biomolecule adducts, each having specific photophysical and pharmaco-chemical properties, as a contrast medium for fluorescence and transillumination diagnostics in the NIR range, to new dyes and pharmaceuticals containing such dyes.
1. A cyanine dye as represented by the general formula IIa:
wherein
r represents the numbers 0, 1 or 2, wherein, for r=2, the respective L 6 and L 7 groups that occur in duplicate may be the same or different, L 1 to L 7 are the same or different, each independently representing a CH or CR group,
where
R is a halogen atom, a hydroxy, carboxy acetoxy, amino, nitro, cyano or sulfonic acid group or an alkyl, alkenyl, hydroxyalkyl, carboxyalkyl, alkoxy, alkoxycarbonyl, sulfoalkyl, alkylamino, dialkylamino or halogenalkyl group containing up to 6 carbon atoms, aryl, alkylaryl, hydroxyaryl, carboxyaryl, sulfoaryl, arylamino, diarylamino, nitroaryl or halogenaryl group containing up to 9 carbon atoms, or where R represents a bond that bonds to another group R and forms a 4- to 6-member ring together with the interspersed groups L 1 to L 7 , or two of L 1 and L 7 that are linked via a —CO— group,
R 3 to R 12 are the same or different, each independently representing a hydrogen atom, a group B or W, or an alkyl or alkenyl group containing up to 6 carbon atoms or an aryl or aralkyl group optionally carrying an additional group W, or to each pair of adjacent groups R 3 to R 10 are annealed, with due regard for the interspersed C atoms, 5- to 6-member rings that may be saturated, unsaturated or aromatic, and that optionally carry an additional group R, and X and Y are the same or different, each independently representing an O, Se or Te or a —C(CH 3 ) 2 —, —CH═CH— or —CR 13 R 14 — group, wherein at least one of R 3 to R 12 comprises a group W,
where R 13 and R 14 independently represent a hydrogen atom, a group B or W, or an alkyl or alkylene group containing up to 6 carbon atoms or an aryl or aralkyl group containing up to 9 carbon atoms, the alkyl, alkenyl, aryl or aralkyl group optionally carrying an additional group W,
wherein at least one of R 3 to R 14 is a group B,
wherein B is a biological detecting unit having a molecular weight of up to 30,000 that bonds to specific cell populations or selectively to receptors, or accumulates in tissues or tumors, and W is a hydrophilic group that improves water-solubility selected from the group consisting of
(i) a carboxylic acid group;
(ii) a sulfonic acid group;
(iii) a carboxyalkyl group;
(iv) an alkoxycarbonyl or alkoxyoxoalkyl group containing up to 12 carbon atoms; and
(v) a group of the general formula III
—(CH 2 ) n -O—Z or —(CH 2 —CH 2 —O) a -Z (III)
wherein
a represents the numbers 0 to 6,
Z represents a hydrogen atom or an alkyl group containing 3 to 6 C atoms having 2 to n−1 hydroxy groups, with n being the number of C atoms or an aryl or aralkyl group containing 6 to 10 C atoms and having 2 to 4 additional hydroxy groups, or an alkyl group containing 1 to 6 C atoms and having 1 to 3 additional carboxy groups, or an aryl group containing 6 to 9 C atoms and having 1 to 3 additional carboxyl groups or an aralkyl group or a nitroaryl or a nitroaralkyl group containing 6 to 15 C atoms;
(vi) a group of the general formulas IIIa or IIIb;
(vii) a group of the general formula IIIc;
—(CH 2 ) o -(CO) p -NR 1 —(CH 2 ) s -(NH—CO) q -R 2 (IIIc)
wherein
o and s independently represent the numbers 0, 1, 2, 3, 4, 5 or 6,
p and q independently represent 0 or 1,
R 1 and R 2 independently represent a group Z except the substituents of the general formulas IIIa and IIIb, or independently represent a group of the general formulas IIId or IIIe
wherein p and q=1; and
(viii) a group of the general formula III as defined above, wherein R 11 and R 12 do not comprise a carboxyalkyl group.
2. A near infrared imaging agent comprising a cyanine dye represented by the general formula IIa:
wherein
r represents the numbers 0, 1 or 2, wherein, for r=2, the respective L 6 and L 7 groups that occur in duplicate may be the same or different, L 1 and L 7 are the same or different, each independently representing a CH or CR group, where
R is a halogen atom, a hydroxy, carboxy acetoxy, amino, nitro, cyano or sulfonic acid group or an alkyl, alkenyl, hydroxyalkyl, carboxyalkyl, alkoxy, alkoxycarbonyl, sulfoalkyl, alkylamino, dialkylamino or halogenalkyl group containing up to 6 carbon atoms, aryl, alkylaryl, hydroxyaryl, carboxyaryl, sulfoaryl, arylamino, diarylamino, nitroaryl or halogenaryl group containing up to 9 carbon atoms, or where R represents a bond that bonds to another group R and forms a 4- to 6-member ring together with the interspersed groups L 1 and L 7 , or two of L 1 to L 7 that are linked via a —CO— group,
R 3 to R 12 are the same or different, each independently representing a hydrogen atom, a group B or W, or an alkyl or alkenyl group containing up to 6 carbon atoms or an aryl or aralkyl group optionally carrying an additional group W, or to each pair of adjacent groups R 3 to R 10 are annealed, with due regard for the interspersed C atoms, 5- to 6-member rings that may be saturated, unsaturated or aromatic, and that optionally carry an additional group R, and X and Y are the same or different, each independently representing an O, Se or Te or a —C(CH 3 ) 2 —, —CH═CH— or CR 13 R 14 — group, wherein at least one of R 3 to R 12 is a group W,
where R 13 and R 14 independently represent a hydrogen atom, a group B or W, or an alkyl or alkylene group containing up to 6 carbon atoms or an aryl or aralkyl group containing up to 9 carbon atoms, the alkyl, alkenyl, aryl or aralkyl group optionally carrying an additional group W,
wherein at least one of R 3 to R 14 is a group B,
wherein B is a biological detecting unit having a molecular weight of up to 30,000 that bonds to specific cell populations or selectively to receptors, or accumulates in tissues or tumors, and W is a hydrophilic group that improves water-solubility selected from the group consisting of
(i) a carboxylic acid group;
(ii) a sulfonic acid group;
(iii) a carboxyalkyl group;
(iv) an alkoxycarbonyl or alkoxyoxoalkyl group containing up to 12 carbon atoms; and
(v) a group of the general formula III
—(CH 2 ) n -O—Z or —(CH 2 —CH 2 —O) a -Z (III)
wherein
a represents the numbers 0 to 6,
Z represents a hydrogen atom or an alkyl group containing 3 to 6 C atoms having 2 to n−1 hydroxy groups, with n being the number of C atoms or an aryl or aralkyl group containing 6 to 10 C atoms and having 2 to 4 additional hydroxy groups, or an alkyl group containing 1 to 6 C atoms and having 1 to 3 additional carboxy groups, or an aryl group containing 6 to 9 C atoms and having 1 to 3 additional carboxyl groups or an aralkyl group or a nitroaryl or a nitroaralkyl group containing 6 to 15 C atoms;
(vi) a group of the general formulas IIa or IIIb:
(vii) a group of the general formula IIIc;
—(CH 2 ) o -(CO) p -(CH 2 ) s -(NH—CO) q -R 2 (IIIc)
wherein
o and s independently represent the numbers 0, 1, 2, 3, 4, 5 or 6,
p and q independently represent 0 or 1,
R 1 and R 2 independently represent a group Z except the substituents of the general formulas IIIa and IIIb, or independently represent a group of the general formulas IIId or IIIe
wherein p and q=1; and
(viii) a group of the general formula III as defined above, wherein R 11 and R 12 do not comprise a carboxyalkyl group;
wherein R 11 and R 12 do not comprise a carboxyalkyl group.
3. A near infrared imaging agent comprising a cyanine dye represented by the general formula IIa:
wherein
r represents the numbers 0, 1 or 2, wherein, for r=2, the respective L6 and L7 groups that occur in duplicate may be the same or different, L 1 and L 7 are the same or different, each independently representing a CH or CR group, where
R is a halogen atom, a hydroxy, carboxy acetoxy, amino, nitro, cyano or sulfonic acid group or an alkyl, alkenyl, hydroxyalkyl, carboxyalkyl, alkoxy, alkoxycarbonyl, sulfoalkyl, alkylamino, dialkylamino or halogenalkyl group containing up to 6 carbon atoms, aryl, alkylaryl, hydroxyaryl, carboxyaryl, sulfoaryl, arylamino, diarylamino, nitroaryl or halogenaryl group containing up to 9 carbon atoms, or where R represents a bond that bonds to another group R and forms a 4- to 6-member ring together with the interspersed groups L 1 and L 7 , or two of L 1 and L 7 that are linked via a —CO— group,
R 3 to R 12 are the same or different, each independently representing a hydrogen atom, a group B or W, or an alkyl or alkenyl group containing up to 6 carbon atoms or an aryl or aralkyl group optionally carrying an additional group W, or to each pair of adjacent groups R 3 to R 10 are annealed, with due regard for the interspersed C atoms, 5- to 6-member rings that may be saturated, unsaturated or aromatic, and that optionally carry an additional group R, and X and Y are the same or different, each independently representing an O, Se or Te or a —C(CH 3 ) 2 —, —CH═CH— or —CR 13 R 14 — group, wherein at least one of R 3 to R 12 is a group W,
where R 13 and R 14 independently represent a hydrogen atom, a group B or W, or an alkyl or alkylene group containing up to 6 carbon atoms or an aryl or aralkyl group containing up to 9 carbon atoms, the alkyl, alkenyl, aryl or aralkyl group optionally carrying an additional group W,
wherein at least one of R 3 to R 14 is a group B,
wherein B is a macromolecular group that non-selectively bonds to specific cell populations or selectively to receptors, or accumulates in tissues or tumors, and W is a hydrophilic group that improves water-solubility selected from the group consisting of
(i) a carboxylic acid group;
(ii) a sulfonic acid group;
(iii) a carboxyalkyl group;
(iv) an alkoxycarbonyl or alkoxyoxoalkyl group containing up to 12 carbon atoms; and
(v) a group of the general formula III
—(CH 2 ) n -O—Z or —(CH 2 —CH 2 —O) a -Z (III)
wherein
a represents the numbers 0 to 6,
Z represents a hydrogen atom or an alkyl group containing 3 to 6 C atoms having 2 to n−1 hydroxy groups, with n being the number of C atoms or an aryl or aralkyl group containing 6 to 10 C atoms and having 2 to 4 additional hydroxy groups, or an alkyl group containing 1 to 6 C atoms and having 1 to 3 additional carboxy groups, or an aryl group containing 6 to 9 C atoms and having 1 to 3 additional carboxyl groups or an aralkyl group or a nitroaryl or a nitroaralkyl group containing 6 to 15 C atoms;
(vi) a group of the general formulas IIIa or IIIb;
(vii) a group of the general formula IIIc;
—(CH 2 ) o -(CO) p -NR 1 —(CH 2 ) s -(NH—CO) q -R 2 (III)
wherein
o and s independently represent the numbers 0, 1, 2, 3, 4, 5 or 6,
p and q independently represent 0 or 1,
R 1 and R 2 independently represent a group Z except the substituents of the general formulas IIIa and IIIb, or independently represent a group of the general formulas IIId or IIIe
wherein p and q=1; and
(viii) a group of the general formula III as defined above, wherein R 11 and R 12 do not comprise a carboxyalkyl group; and wherein R 11 and R 12 do not comprise a carboxyalkyl group.
4. A cyanine dye 2-[7-[1,3-dihydro-3,3-dimethyl-1-(4-sulfobutyl)-2H-indol-2-ylidene]-1,3,5-heptatrienyl]-3,3-dimethyl-5-(methoxypolyoxyethylene)aminocarbonyl-1-(4-sulfobutyl)-3H-indolium, sodium salt.