# US 9,040,721 B2 · Halogenated compounds for Photodynamic therapy

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- Number: US 9,040,721 B2
- Document ID: US9040721B2
- Status: Granted
- Kind: B2
- Application number: 14/270,067
- Filed: 2014-05-05
- Published: 2014-08-28
- Granted: 2015-05-26
- Earliest claimed: 2012-03-03
- Assignees: Nanoquantum Sciences, Inc.
- Applicants: Nanoquantum Sciences, Inc.
- Inventors: Gary W. Jones; Anatoliy L. Tatarets; Leonid D. Patsenker
- Web page: https://patentgrep.com/patent/US9040721B2

## CPC

- A61K 41/0057: {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}
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/438: The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
- A61K 41/0071: {PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines}
- A61N 1/30: Apparatus for iontophoresis, {i.e. transfer of media in ionic state by an electromotoric force into the body}, or cataphoresis
- A61N 5/062: {Photodynamic therapy, i.e. excitation of an agent}
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/04: Indoles; Hydrogenated indoles
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 209/10: with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D 209/18: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/24: with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
- C07D 209/58: [b]- or [c]-condensed
- C07D 209/60: Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
- C07D 277/62: Benzothiazoles
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 293/12: Selenazoles; Hydrogenated selenazoles
- C07D 401/02: containing two hetero rings
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/14: containing three or more hetero rings
- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 471/10: Spiro-condensed systems
- C07D 487/22: in which the condensed system contains four or more hetero rings
- C09B 23/086: {more than five >CH- groups}
- C09B 23/105: {two >CH- groups}
- C09B 47/00: Porphines; Azaporphines {(non-dyeing compounds C07D487/22)}
- C09B 62/00: Reactive dyes, i.e. dyes which form covalent bonds with the substrates or which polymerise with themselves
- A61N 2005/0659: {infrared}
- A61N 2005/0663: {Coloured light}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C09B: ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES {, e.g. PIGMENTS}; MORDANTS; LAKES (fermentation or enzyme using processes to synthesise a desired chemical compound C12P)

## Abstract

Halo-organic heterocyclic compounds are described, in which at least two halogen atoms are bound to a nitrogen-containing heterocyclic terminal moiety of the compound, with at least one of such halogen atoms being iodine or bromine. Also described are polymethine dyes based on these heterocyclic compounds, and dendrimeric compounds and conjugates of such polymethine dyes. The polymethine dyes are characterized by enhanced properties, e.g., brightness, photostability, sensitivity and/or selective affinity that make them useful to target cancer cells, pathogenic microorganisms, and/or other biological materials, in applications such as photodynamic therapy, photodynamic antimicrobial chemotherapy (PACT), cancer treatment, selective removal or attachment of biological materials, antimicrobial coating materials, and other diagnostic, theranostic, spectrum shifting, deposition/growth, and analytic applications.

## Claims

### Claim 1

A dye comprising at least one of moieties Het and Het+, wherein Het and Het+ have the formulae:
wherein:
each of X1, X2, X3, and X4 is independently C—RX;
RX is H, F, Cl, Br, I, L-Sc, L-RR, L-R±; aliphatic, alicyclic, or aromatic group; amino or substituted amino; sulfo, trifluoromethyl, hydroxy, alkoxy, carboxy, phosphate, phosphonate, or sulfate; or adjacent RX substituents, taken in combination, form a fused aromatic or heterocyclic ring that is itself optionally further substituted by H, F, Cl, Br, I, L-Sc, L-RR, L-R±; aliphatic, alicyclic, or aromatic group; amino or substituted amino; sulfo, trifluoromethyl, hydroxy, alkoxy, carboxy, phosphate, phosphonate, or sulfate;
RN is selected from H, L-Sc, L-RR, L-R±, aliphatic groups, alicyclic groups, alkylaryl groups, and aromatic groups, wherein each aliphatic residue may incorporate up to ten heteroatoms selected from N, O, and S, and can be substituted one or more times by F, Cl, Br, I, hydroxy, alkoxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, alkyl-amino, dialkyl-amino or trialkylammonium;
Y is O, S, Se, Te, C(RC1)(RC2), or N—RN2;
each RC1 and RC2 is independently RC, or adjacent substituents (RC1, RC2) form a cyclic or heterocyclic system that further may be substituted or fused;
RC is H, L-Sc, L-RR, L-R±, aliphatic, alicyclic, aromatic, heteroatom-substituted aliphatic, polyether, alkyl-aryl, aryl-alkyl, F, Cl, Br, I, NH2, —COOH, —CN, azido, —OH, —NO2, —SO3H, —SO2NHRm, —SO2NHN(Rm)2, sulfone, —C6H4—SO3H, —C6H4—PO3H, —CH2—C6H4—SO3H, —CH2—C6H4—PO3H, pyridylium, pyrylium, —PO(OH)2, —O—PO(OH)2, —PO(OH)(ORm), —O—P(OH)(ORm), PO(ORm)2, —(CH2CH2O)nPO(ORm)2, —(OCH2CH2)nPO(ORm)2, wherein n=1-30, —CONH2, —CON(Rm)2, —CONHN(Rm)2, —COO—NHS or —COO—Rm, wherein Rm is selected from a group consisting of H, L-Sc, L-RR, L-R±, aliphatic substituents, and aromatic substituents, and each aliphatic residue may incorporate up to ten heteroatoms selected from N, O, S, and can be substituted by F, Cl, Br, I, hydroxy, alkoxy, carboxy, sulfo, phosphate, amino, sulfate, phosphonate, cyano, nitro, azido, alkyl-amino, dialkyl-amino or trialkylammonium;
L is a single covalent bond or is a covalent linkage that is linear or branched, cyclic or heterocyclic, saturated or unsaturated, having 1-20 non-hydrogen atoms selected from the group consisting of C, N, P, O and S, arranged so that the linkage contains any combination of ether, thioether, amine, ester, amide bonds; single, double, triple or aromatic carbon-carbon bonds; or carbon-sulfur bonds, carbon-nitrogen bonds, phosphorus-sulfur, nitrogen-nitrogen, nitrogen-oxygen or nitrogen-platinum bonds, or aromatic or heteroaromatic bonds;
RR is a reactive group;
Sc is a moiety that is conjugated to ring A through linker, L, and is selected from the group consisting of alkanes, alkenes, alkynes, polyethers, polyamines, cycloparaffins, cycloolefins, cyclynes, heteroalicyclic groups, aromatic groups, heteroaromatic groups, organic dyes, polymethines, dendrimers, nanoparticles, biological molecules, and biological compounds, and wherein the alkanes, alkenes, alkynes, polyethers, polyamines, cycloparaffins, cycloolefins, cyclynes, heteroalicyclic groups, aromatic groups, heteroaromatic groups, organic dyes, polymethines, and dendrimers are optionally substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, carboxylic acid, sulfonic acid, CN, nitro, hydroxy, phosphate, phosphonate, sulfate, cyano, azido, amine, alkyl, alkoxy, trialkylammonium and aryl;
R± is an ionic or hydrophilic group;
RN1, RN2 and RN3 may be independently selected from the substituents RN; and
ring A is an aromatic or heterocyclic ring having at least two halo substituents thereon, wherein at least one of said halo substituents is iodine or bromine, with the proviso that when the number of halo substituents on ring A is two, and one of the halo substituents is iodine, the other is not chlorine.

### Claim 2 (depends on 1)

The dye of claim 1, wherein at least one of said halo substituents is iodine.

### Claim 3 (depends on 1)

The dye of claim 1, wherein at least one of said halo substituents is bromine.

### Claim 4 (depends on 1)

The dye of claim 1, comprising both Het and Het+ moieties.

### Claim 5 (depends on 1)

The dye of claim 1, comprising at least one of the moieties Ind and Ind+, wherein Ind and Ind+ have the formulae:
wherein:
Rh1, Rh2, Rh3 and Rh4 are each independently RX with the proviso that at least two of Rh1, Rh2, Rh3 and Rh4 are halo and at least one of Rh1, Rh2, Rh3, and Rh4 is iodine or bromine.

### Claim 6 (depends on 1)

The dye of claim 1, wherein Het is
and Het+ is
wherein:
Rh2 is H, I, Br, alkoxy, sulfo, or —(CH2)mCOOH, wherein m=0-20;
RC1 is alkyl, —(CH2)n—COOH, —(CH2)n—SO3H, —(CH2)n—PO(OEt)2, —(CH2)n—PO(OH)(OEt), or —(CH2)n—PO(OH)2, wherein n=1-20;
RN1 is alkyl, —(CH2)k—COOH, —(CH2)k—SO3H, —(CH2)k—PO(OEt)2, —(CH2)k—PO(OH)(OEt), or —(CH2)k—PO(OH)2, wherein k=1-20.

### Claim 7 (depends on 1)

The dye of claim 1, wherein Het is
and Het+ is
wherein:
Rh2 is H, I, Br, alkoxy, sulfo, or —(CH2)mCOOH, wherein m=0-20;
RC1 is alkyl, —(CH2)n—COOH, —(CH2)n—SO3H, —(CH2)n—PO(OEt)2, —(CH2)n—PO(OH)(OEt), or —(CH2)n—PO(OH)2, wherein n=1-20;
RN1 is alkyl, —(CH2)k—COOH, —(CH2)k—SO3H, —(CH2)k—PO(OEt)2, —(CH2)k—PO(OH)(OEt), or —(CH2)k—PO(OH)2, wherein k=1-20.

### Claim 8 (depends on 1)

The dye of claim 1, comprising at least one of the moieties
wherein:
Rh1, Rh2, Rh3 and Rh4 are each independently RX with the proviso that at least two of Rh1, Rh2, Rh3 and Rh4 are halo and at least one of Rh1, Rh2, Rh3, and Rh4 is iodine or bromine; and
Y is S or Se.

### Claim 9 (depends on 1)

The dye of claim 1, wherein Het is comprised in a moiety
and Het+ is comprised in a moiety
wherein:
at least one of said halo substituents is iodine or bromine;
n=0-5;
each of R1, R2 and R3 is independently selected from H, F, Cl, Br, I, L-Sc, L-RR, L-R±, aliphatic group, alicyclic group, heteroatom-substituted aliphatic group, aromatic group, polyether, cyano, carboxy, carboxamide, carboxylic ester, formyl, amine group, nitro, sulfonic acid, phosphonic acid, phosphonic ester, sulfone, and sulfamide, or (R1 and RC1) or (R1 and RC2) form a cyclic or heterocyclic system, which further may be substituted or fused, or (R1 and R2) or (R1 and R3) or (R2 and R3) form a cyclic or heterocyclic system, which further may be substituted or fused;
W1 is an aromatic or heterocyclic group selected from the group consisting of the following structures:
W2 is an aromatic or heterocyclic group selected from the group consisting of the following structures:
substituents X1, X2, X3, X4, Y, YW, RN1, RAr1, RAr2, RAr3, RAr4, RAr5, and RAr6 in W1 and W2 can be independently the same or different;
Y and YW are independently selected from O, S, Se, Te, CRC1)(RC2) and N—RN2;
Yp is 0, S, Se, Te, or N—RN2; and
RAr1, RAr2, RAr3, RAr4, RAr5, RAr6 are each independently RX or any adjacent substituents RAr1, RAr2, RAr3, RAr4, RAr5, and RAr6 may form a cycle or heterocycle, which when sterically and stoichiometrically permitted may optionally be further substituted or fused.

### Claim 10 (depends on 1)

The dye of claim 1, wherein Het is comprised in a moiety
and Het+ is comprised in a moiety
wherein:
at least one of said halo substituents is iodine or bromine;
n=0-5;
R1 and R3 are each independently selected from H, F, Cl, Br, I, L-Sc, L-RR, L-R±, aliphatic group, alicyclic group, heteroatom-substituted aliphatic group, aromatic group, polyether, cyano, carboxy, carboxamide, carboxylic ester, formyl, amine group, nitro, sulfonic acid, phosphonic acid, phosphonic ester, sulfone, and sulfamide, or (R1 and RC1) or (R1 and RC2) may form a cyclic or heterocyclic system, which further may be substituted or fused, or R1 and R3 may form a cyclic or heterocyclic system, which further may be substituted or fused;
W1 is an aromatic or heterocyclic group selected from the group consisting of the following structures:
W2 is an aromatic or heterocyclic group selected from the group consisting of the following structures:
substituents RN1, RN2, RAr1, RAr2, RAr3, RAr4, RAr5, RAr6 in W1 and W2 can be independently the same or different;
YN1 is OH, ORY1, SH, SRY1, or N(RY1RY2);
RY1 and RY2 are each independently RN or adjacent substituents (RY1, RY2) and/or (RY1, RAr2) and/or (RY2, RAr3), where sterically and stoichiometrically feasible, may form a cycle, which further may be substituted or fused; and
YN2 is O, S, or +N(RY1RY2).

### Claim 11 (depends on 1)

The dye of claim 1, wherein Het is comprised in a moiety
and Het+ is comprised in a moiety
wherein:
at least one of said halo substituents is iodine or bromine;
Z1 is O, S, Se, Te, C(Ra1)(Rb1), N—RN;
Ra1 and Rb1 are each independently selected from the group consisting of hydrogen, aliphatic, heteroatom-substituted aliphatic, polyether, aromatic, reactive aliphatic, and reactive aromatic groups, carboxylic acid, carboxamide, carboxylic ester, cyano, nitro, aliphatic amine groups, sulfonic acid, phosphonic acid, phosphonic ester, sulfone, or sulfamide, or adjacent substituents Ra1 and Rb1 may form a cyclic or heterocyclic system which further may be substituted or fused;
Z2 is O−, S−, Se−, Te−, O—RN, or S—RN, or Z2 is N(Ra2)(Rb2) when at least one of substituents Ra2 or Rb2 contains at least one reactive group; and
Ra2 and Rb2 are each independently RN or adjacent substituents (Ra2, Rb2) may form a cycle.

### Claim 12 (depends on 1)

The dye of claim 1, comprising a linker L selected from the group consisting of linkers of the following formulae 1-4:
—(CH2CH2O)n—, wherein n=1-20; 1
2
wherein p=1-20;
3
wherein m=1-20, n=1-20, p=1-20; and
4
wherein k=0-10.

### Claim 13 (depends on 1)

The dye of claim 1, selected from the group consisting of dyes of the following formulae 1-18:

### Claim 14 (depends on 1)

A dendrimeric compound comprising the dye of claim 1.

### Claim 15 (depends on 1)

A composition comprising the dye of claim 1, or a conjugate thereof.

### Claim 16 (depends on 15)

The composition of claim 15, wherein the dye comprises a counterion, or a counterionic dye is covalently bonded to the dye, for enhanced sensitizing efficiency.

### Claim 17 (depends on 15)

The composition of claim 15, wherein the dye comprises at least one reactive group substituent enabling covalent or non-covalent bonding of the dye to another molecule or to a particle, or wherein the dye is bound to a carrier molecule, to a particle, or to a nanoparticle.

### Claim 18 (depends on 15)

The composition of claim 15, wherein the dye is selected from the group consisting of cyanine dyes, squaraine dyes, croconium dyes, merocyanine dyes, and stryryl dyes.

### Claim 19 (depends on 15)

The composition of claim 15, wherein the dye is:
(i) conjugated with another dye of a same or different type in a molecular conjugate having at least one of increased fluorescence and increased ROS efficiency, in relation to a corresponding composition comprising a corresponding non-conjugated dye;
(ii) present in a conjugated or unconjugated form, and the dye and/or a conjugate thereof comprises at least one binding site effective to bind with at least one pathogen selected from the group consisting of bacteria, virus, molds, proteomes, and spores, and wherein the dye and/or conjugate thereof is hydrophilic; or
(iii) present in a conjugated or unconjugated form, and the dye and/or a conjugate thereof comprises at least one binding site effective to bind with at least one toxin, and wherein the dye and/or conjugate thereof is hydrophilic.

### Claim 20 (depends on 15)

The composition of claim 15, wherein the dye has at least one photosensitizing characteristic selected from the group consisting of absorption maxima, emission maxima, emission intensity, and sensitizing efficiency, which is/are changed upon exposure of the dye to light.