Cyanine dye compound and preparation method therefor, and dual-function agent for photodynamic therapy and preparation method therefor

Patent metadata

Field	Value
Publication number	US-9821062-B2
Application number	US-201314758427-A
Country	US
Kind code	B2
Filing date	Feb 6, 2013
Priority date	Dec 28, 2012
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Disclosed are a cyanine dye compound and a preparation method therefor, and a dual-function agent for photodynamic therapy and a preparation method therefor. The provided cyanine dye compound is connected to multiple markers, which improves the accuracy of combination of dye and tumor cells, effectively reduces the background value, and avoids excessive residues in the liver. The provided cyanine dye compound is conjugated with the photosensitizer at 2′″ position, so that tumor highly absorbs the conjugates.

First claim

The invention claimed is:

1. A compound having a structure as shown in formula I,

wherein R 1 and R 2 are independently selected from hydrogen, alkaryl, fluorinated groups, and sulfonated groups;
R 3 and R 4 are independently selected from —H, —SO 3 H, —SO 3 Na, —COOH, —OH, and —NH 2 ;
X is NH 2 ;
Y is selected from —O— and —S—; alternatively, Y is absent, being a single bond;
Z is selected from —COOH, —COOEt, and —CO—NH-A 4 ;
A 4 is —C 6 H 5 , —(CH 2 ) n -PS, in which n=0 to 6; and PS is glycosyl, tetrapyrrole ring or reduced tetrapyrrole ring, RGD peptide, iRGD peptide, DOTA or DTPA;
the tetrapyrrole ring includes, but is not limited to, chlorin, bacteriochlorin, purpurin imide and rhodopurpurin imide.

2. The compound according to claim 1 , wherein the compound has a structure as shown in formula II,

wherein X is —NH 2 ;
Z is any one of —COOH, —COOEt, and —CO—NH-A 4 ;
A 4 is —C 6 H 5 , DOTA, or DTPA.

3. The compound according to claim 2 , wherein the compound has a structure as shown in any one of formula IV to formula VII, and Formula X,

4. The compound according to claim 1 , wherein the compound has a structure as shown in formula XI,

wherein Y is O or S; alternatively, Y is absent, being a single bond;
R 1 and R 2 are independently selected from hydrogen, alkaryl, fluorinated groups or sulfonated groups;
R 3 and R 4 are independently selected from —H, —SO 3 H, —SO 3 Na, —COOH, —OH or —NH 2 ;
A 1 is —H;
A 4 is —(CH 2 ) n -PS, in which n=0 to 6; and PS is glycosyl, tetrapyrrole ring or reduced tetrapyrrole ring, RGD peptide, iRGD peptide, DOTA, or DTPA;
the tetrapyrrole ring includes, but is not limited to, chlorin, bacteriochlorin, purpurin imide and rhodopurpurin imide.

5. The compound according to claim 4 , wherein the compound has a structure as shown in formula XII,

wherein A 4 is RGD peptide, iRGD peptide, glycosyl, DTPA, DOTA, triamino ester or —(CH 2 ) n -PS, in which n=0 to 6, and PS has a structure as shown in formula XIII, formula XIV or formula XV;

wherein represents a single bond or a double bond; Q 1 and Q 2 are independently —O—, alkyl, aryl or reduced aryl; R 5 and R 6 are independently alkyl or alkyl labelled with F-18, iodobenzyl, or iodobenzyl labelled with I-124.

6. The compound according to claim 4 , wherein the compound has a structure as shown in formula XVI or formula XVII,

7. A preparation method for the compound of claim 3 having a structure as shown in formula III, formula IV, formula V, formula VIII or formula IX, wherein the method comprises steps of:
step 1: subjecting a compound having a structure as shown in formula XXIII to a first Vilsmeier-Haack-Arnold reaction in the presence of phosphoryl chloride, DMF and aniline, to produce a compound having a structure as shown in formula XXIV;
step 2: subjecting the compound having the structure as shown in formula XXIV to a first substitution reaction with a compound having a structure shown in formula XXV, to produce an intermediate having a structure shown in formula XVIII, formula XIX or formula XX; and
step 3: subjecting the intermediate having the structure shown in formula XVIII, formula XIX or formula XX to a fourth substitution reaction with a compound having a structure shown in formula XXVII, respectively, to obtain the compound having the structure as shown in formula III, formula IV, formula V, formula VIII or formula IX;

wherein R 7 is selected from —H,

or —COOH; R 8 is selected from —H,

or —COOH; and X is selected from —H, —COOH or —NH 2 .

8. A preparation method for the compound of claim 3 having a structure as shown in formula X, wherein the method comprises steps of:
step 1: subjecting a compound having a structure as shown in formula XXIII to a third Vilsmeier-Haack-Arnold reaction in the presence of phosphoryl chloride, DMF and aniline, to produce a compound having a structure as shown in formula XXIV;
step 2: subjecting the compound having the structure as shown in formula XXIV to a fifth substitution reaction with a compound having a structure shown in formula XXV, to produce an intermediate having a structure shown in formula XIX; and
step 3: subjecting the intermediate having the structure shown in formula XIX to a sixth substitution reaction with 4-aminophenylboronic acid under the catalysis of Pd(PPh 3 ) 4 , to obtain the compound having the structure as shown in formula X;

wherein R 7 is —COOH; and R 8 is

9. A preparation method for a compound having a structure as shown in formula VI, formula VII or formula XVII, wherein the method comprises steps of:
step 1: subjecting 4-carboxyl cyclohexanone to a second Vilsmeier-Haack-Arnold reaction in the presence of phosphoryl chloride and DMF, to produce a compound having a structure as shown in formula XXVI;
step 2: subjecting the compound having the structure as shown in formula XXVI to a second substitution reaction with a compound having a structure shown in formula XXV, to produce an intermediate having a structure shown in formula XXI;
step 3: subjecting the intermediate having the structure shown in formula XXI to a third substitution reaction with a compound having a structure shown in formula XXVII, DOTA-NH 2 or DTPA-NH 2 in the presence of BOP and DMF, to produce an intermediate having a structure shown in formula XXIX, formula XXX or formula XXXI; and
step 4: subjecting the intermediate having the structure as shown in formula XXIX, formula XXX or formula XXXI to a seventh substitution reaction with 4-aminothiophenol, to obtain the compound having the structure as shown in formula VI, formula VII or formula XVII;

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Pandey Ravindra K
• Patel Nayan
• Ethirajan Manivannan
• Bai Hua
• Chen Zhenliang

Classifications

• C09B23/0033

  the substituent being bound through a sulfur atom · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C09B23/0066

  the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid) · CPC title

• C07D209/60

  Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles · CPC title