Non-benzenoid aromatic systems for imaging, monitoring and therapy

Patent metadata

Field	Value
Publication number	US-10059739-B2
Application number	US-201514950928-A
Country	US
Kind code	B2
Filing date	Nov 24, 2015
Priority date	Sep 11, 2009
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

This invention is directed to non-benzenoid aromatic compounds. Other aspects include methods of using non-benzenoid aromatic compounds for imaging and phototherapeutic uses thereof. Non-benzenoid compounds provided herein generally have one or more substituent groups which allow tailoring of the spectral properties or provide photoreactivity or targeting ability.

First claim

What is claimed is:

1. A compound of the formula (FX10):

wherein:
each of L 2 to L 8 is independently selected from C 1 -C 10 alkylene, C 3 -C 10 cycloalkylene, C 2 -C 10 alkenylene, C 3 -C 10 cycloalkenylene, C 2 -C 10 alkynylene, ethenylene, ethynylene, phenylene, 1-aza-2,5-dioxocyclopentylene, (CH 2 CH 2 O) m —, —(CHOH) m —, or 1,4-diazacyclohexylene;
each m is independently selected from an integer selected from the range of 1 to 100;
each q is independently selected from 0 or 1;
each of W 2 to W 8 is independently selected from a single bond, —(CH 2 ) n —, —O(CH 2 ) n —, —(CH 2 ) n O—, —(HCCH) n —, —O—, —S—, —SO—, —SO 2 —, —SO 3 —, —OSO 2 —, —NR 9 —, —CO—, —COO—, —OCO—, —OCOO—, —CONR 10 —, —NR 11 CO—, —OCONR 12 —, —NR 13 COO—, —NR 14 CONR 15 —, —NR 16 CSNR 17 , —O(CH 2 ) n —, —NR 18 (CH 2 ) n —, —CO(CH 2 ) n —, —COO(CH 2 ) n —, —OCO(CH 2 ) n —, —OCOO(CH 2 ) n —, —CONR 19 (CH 2 ) n —, —CONR 20 (CH 2 ) n (OCH 2 CH 2 ) u —, —NR 21 CO(CH 2 ) n —, —OCONR 22 (CH 2 ) n —, —NR 23 COO(CH 2 ) n —, —NR 24 CONR 25 (CH 2 ) n —, —NR 26 CSNR 27 (CH 2 ) n —, —O(CH 2 ) n NR 28 CO(CH 2 ) n —, —CO(CH 2 ) n (CH 2 OCH 2 ) n (CH 2 ) n NR 29 (CH 2 ) n NR 30 CO—, —NR 69 SR 70 —, or —CO(CH 2 ) n NR 31 CO—;
each n is independently selected from an integer selected from the range of 1 to 10;
each of R 9 to R 31 and each of R 69 to R 70 is independently selected from hydrogen, C 1 -C 20 alkyl, or C 5 -C 30 aryl;
each R 3 to R 8 is independently selected from hydrogen, C 1 -C 20 alkyl, C 5 -C 30 aryl, C 3 -C 20 acyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, C 5 -C 20 alkylaryl, C 1 -C 6 alkoxycarbonyl, halo, halomethyl, dihalomethyl, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —OSR 37 —, —SO 2 R 38 , —SO 2 OR 39 , —SO 2 NR 40 R 41 , —PO 3 R 42 R 43 , —OR 44 , —SR 45 , —NR 46 R 47 , —NR 48 COR 49 , —CH 2 (CHOH) n R 50 , —(CH 2 CH 2 O) n R 51 , —CH(R 52 )CO 2 H, —CH(R 53 )NH 2 , TG 1 to TG 8 , PS 1 to PS 8 , or FL 1 to FL 8 ;
R 2 is TG 1 , PS 1 or FL 1 ;
each u is independently selected from an integer selected from the range of 1 to 25;
each of R 32 to R 55 is independently selected from hydrogen or C 1 -C 10 alkyl;
each of TG 1 to TG 8 is independently selected from an amino acid, a peptide, a protein, a nucleoside, a nucleotide, an enzyme, a carbohydrate, a glycomimetic, an oligomer, a lipid, a polymer, an antibody, an antibody fragment, a mono- or polysaccharide comprising 1 to 50 carbohydrate units, a glycopeptide, a glycoprotein, a peptidomimetic, a drug, a drug mimic, a hormone, a receptor, a metal chelating agent, a radioactive or nonradioactive metal complex, a mono- or polynucleotide comprising 1 to 50 nucleic acid units, a polypeptide comprising 2 to 30 amino acid units, or an echogenic agent;
each of PS 1 to PS 8 is independently selected from at least one azide, azo, diazo, oxaza, diaza, dithia, thioxa, dioxa, phthalocyanine, rhodamine, and porphyrin, and wherein each of PS 1 to PS 8 is capable of reacting to produce one or more free radicals selected from nitrenes, carbenes, and singlet oxygen; and
each of FL 1 to FL 8 is independently selected from a fluorescent group selected from the group consisting of a naphthoquinone, an anthracene, an anthraquinone, a phenanthrene, a tetracene, a naphthacenedione, a pyridine, a quinoline, an isoquinoline, an indole, an isoindole, a pyrrole, an imidiazole, a pyrazole, a pyrazine, a purine, a benzimidazole, a benzofuran, a dibenzofuran, a carbazole, an acridine, an acridone, a phenanthridine, a thiophene, a benzothiophene, a dibenzothiophene, a xanthene, a xanthone, a flavone, a coumarin, a phenoxazine, a phenothiazine, a phenoselenazine, a cyanine, an indocyanine, and an azo compound;
wherein any adjacent R 3 to R 8 optionally combines with one or two —CR 54 R 55 groups, to form C 3 -C 7 cycloalkyl, C 3 -C 7 heterocycloalkyl, C 6 aryl, or C 5 -C 6 heteroaryl;
wherein at least one of R 3 to R 8 is C 1 -C 10 alkyl, —OR 44 , —SR 45 , —NR 46 R 47 , or NR 48 COR 49 ; and
wherein at least one of R 3 to R 8 is halo, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —OSR 37 , —SO 2 R 38 , —SO 2 NR 40 R 41 , or C 3 -C 10 acyl; or
wherein at least one of -(L 2 ) q -W 2 —R 2 , (L 3 ) q -W 3 —R 3 , (L 4 ) q -W 4 —R 4 , (L 5 ) q -W 5 —R 5 , (L 6 ) q -W 6 —R 6 , -(L 7 ) q -W 7 —R 7 , or -(L 8 ) q -W 8 —R 8 includes —(OCH 2 CH 2 ) u —.

2. The compound of claim 1 , wherein at least one of R 3 to R 8 is independently selected from C 1 -C 6 alkyl, —OR 44 , —SR 45 , —NR 46 R 47 , or NR 48 COR 49 .

3. The compound of claim 1 , wherein at least one of R 3 to R 8 is independently selected from halo, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —SO 2 R 38 , or —SO 2 NR 40 R 41 .

4. The compound of claim 1 , having R group substituent pairings (R 3 and R 4 ); (R 4 and R 5 ); (R 5 and R 6 ); (R 6 and R 7 ); (R 7 and R 8 ); (R 3 and R 5 ); or (R 4 and R 7 ), wherein one of the identified R groups in the substituent pairings is C 1 -C 10 alkyl, —OR 44 , —SR 45 , —NR 46 R 47 , or NR 48 COR 49 and the other of the identified R groups in the substituent pairings is halo, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —SO 2 R 38 , or —SO 2 NR 40 R 41 .

5. The compound of claim 1 , wherein at least one of R 3 to R 8 is FL 1 , FL 2 , FL 3 , FL 4 , FL 5 , FL 6 , FL 7 or FL 8 , or R 2 is FL 1 .

6. The compound of claim 1 , wherein each of FL 1 to FL 8 is independently selected from a naphthoquinone, an anthraquinone, a naphthacenedione, a pyrazine, an acridine, an acridone, a phenanthridine, a dibenzothiophene, a xanthene, a xanthone, a flavone, a coumarin, a phenoxazine, a phenothiazine, a phenoselenazine, a cyanine, an indocyanine, or an azo compound.

7. The compound of claim 1 , wherein at least one of R 3 to R 8 is PS 1 , PS 2 , PS 3 , PS 4 , PS 5 , PS 6 , PS 7 or PS 8 , or R 2 is PS 1 .

8. The compound of claim 1 , wherein at least one of PS 1 to PS 8 is independently selected from an azide, an azo, a diazo, an oxaza, a diaza, a thioxa, a phthalocyanine, a rhodamine, or a porphyrin group.

9. The compound of claim 1 , wherein at least one of R 3 to R 8 is TG 1 , TG 2 , TG 3 , TG 4 , TG 5 , TG 6 , TG 7 or TG 8 , or R 2 is TG 1 .

10. The compound of claim 1 , wherein each of TG 1 to TG 8 is independently selected from an amino acid, a peptide, a protein, a nucleoside, a nucleotide, an enzyme, an antibody, an antibody fragment, a mono- or polysaccharide comprising 1 to 50 carbohydrate units, a glycopeptide, a peptidomimetic, a drug, a drug mimic, or a hormone.

11. The compound of claim 1 , wherein:
(b) one of R 3 and R 4 is C 1 -C 10 alkyl, —OR 44 , —SR 45 , —NR 46 R 47 , or —NR 48 CO 49 , and the other of R 3 and R 4 is halo, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —SO 2 R 38 , —SO 2 NR 40 R 41 or C 3 -C 10 acyl;
(c) one of R 4 and R 5 is C 1 -C 10 alkyl, —OR 44 , —SR 45 , —NR 46 R 47 , or —NR 48 CO 49 , and the other of R 4 and R 5 is halo, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —SO 2 R 38 , —SO 2 NR 40 R 41 or C 3 -C 10 acyl;
(d) one of R 5 and R 6 is C 1 -C 10 alkyl, —OR 44 , —SR 45 , —NR 46 R 47 , or —NR 48 COR 49 , and the other of R 5 and R 6 is halo, trihalomethyl, —CN, —CO 2 R 32 , —CONR 33 R 34 , —COR 35 , —NO 2 , —SOR 36 , —SO 2 R 38 , —SO 2 NR 40

Assignees

• Medibeacon Inc

Inventors

• Rajagopalan Raghavan

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61K49/0045

  the fluorescent agent being a peptide or protein used for imaging or diagnosis in vivo · CPC title

• C07D261/02

  not condensed with other rings · CPC title

• A61K41/0057 Primary

  Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent · CPC title

• A61K49/0021

  the fluorescent group being a small organic molecule · CPC title