# US 2019/0167794 A1 · Atropisomers of halogenated tetraphenylbacteriochlorins and chlorins and their use in photodynamic therapy

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- Number: US 2019/0167794 A1
- Document ID: US20190167794A1
- Status: Published application
- Kind: A1
- Application number: 15/559,942
- Filed: 2016-03-18
- Published: 2019-06-06
- Earliest claimed: 2015-03-20
- Assignees: Luzitin, S.A.; Universidade De Coimbra
- Applicants: Luzitin, S.A.; Universidade De Coimbra
- Inventors: Nuno Paulo FERREIRA GONCALVES; Tania Patricia CERCA MARTINS DOS SANTOS; Goncalo PEREIRA NASCIMENTO COSTA; Carlos Jorge PEREIRA MONTEIRO; Fabio Antonio SCHABERLE; Sonia CORREIA ALFAR; Artur Carlos REIS DE ABREU; Maria MIGUENS PEREIRA; Luis Guilherme DA SILVA ARNAUT MOREIRA
- Web page: https://patentgrep.com/patent/US20190167794A1

## CPC

- 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}
- A61K 31/409: having four such rings, e.g. porphine derivatives, bilirubin, biliverdine (hemin, hematin A61K31/555)
- A61P 17/06: Antipsoriatics
- A61P 27/02: Ophthalmic agents
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/10: Anthelmintics
- A61P 35/00: Antineoplastic agents
- C07D 487/22: in which the condensed system contains four or more hetero rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This invention relates to atroipsomers of reduced tetraphenylporphyrin derivatives with halogen atoms (F, Cl, Br) in the ortho positions of the phenyl groups, particularly halogenated tetraphenylchlorins and halogenated tetraphenylbacteriochlorins, which can be used in photodynamic therapy. According to the formulae of the invention, the ortho-phenyl substituents X1, X2, X3, X4, X5, X6, X7 and X8 may be identical or different and represent halogen atoms or hydrogen atoms, provided that at least all of X2, X4, X6 and X8 are halogens, and the meta-phenyl substituents R1, R2, R3 and R4 are independently chosen from —OH, —OR or —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR, or —NR2, where R are alkyl of 1 to 12 carbon atoms or R2 represents cycloalkyl with 2 to 12 carbon atoms. The atropisomers of this invention have the majority of the substituents R1, R2, R3 and R4 on the same side of the plane defined by the macrocycle. The invention also relates to an anticancer and/or antimicrobial and/or antiviral pharmaceutical composition where atropisomers α4 and α3β are the main active ingredients, such that the mixture of atropisomers α4 and α3β constitutes more than 70% of the atropisomers present in the active ingredient and/or the atropisomer α4 constitutes more than 20% of the atropisomers present in the pharmaceutical composition.

## Claims

### Claim 1

A pharmaceutical composition comprising atropisomers of the formulae:
wherein:
represents a carbon-carbon single bond or a carbon-carbon double bond;
the bold lines indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist above the plane defined by the macrocycle ring;
X2, X4, X6 and X8 are halogen (F, Cl, Br);
X1, X3, X5 and X7 are halogens (F, Cl, Br) or hydrogen;
R1, R2, R3 and R4 are independently —OH, —OR or —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR or —NR2, where R are alkyl of 1 to 12 carbon atoms or R2 represents cycloalkyl with 2 to 12 carbon atoms;
R5, R6, R7 and R8 are independently H, —OH, —OR, —Cl, or —NHR where R are alkyl of 1 to 12 carbon atoms;
or pharmaceutically acceptable salts thereof;
wherein the relative amount of said atropisomers or their pharmaceutically acceptable salts is more than 70% of the total of atropisomers in the referred pharmaceutical composition.

### Claim 2 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the relative amount of the atropisomer of the formulae:
wherein:
the bold lines indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist above the plane defined by the macrocycle ring;
X2 are independently chosen from halogen (F, Cl, Br);
X1 are independently chosen from halogens (F, Cl, Br) or hydrogen; and
R′ are —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR or —NR2 where R are alkyl of 1 to 12 carbon atoms and R2 represents cycloalkyl with 2 to 12 carbon atoms;
or its pharmaceutically acceptable salts thereof;
is more than 20% of the total of atropisomers in the referred pharmaceutical composition.

### Claim 3 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the relative amounts of the atropisomer of the formulae:
wherein:
the bold lines indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist above the plane defined by the macrocycle ring;
X2 are independently chosen from halogen (F, Cl, Br);
X1 are independently chosen from halogens (F, Cl, Br) or hydrogen; and
R′ are —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR or —NR2 where R are alkyl of 1 to 12 carbon atoms or R2 represents cycloalkyl with 2 to 12 carbon atoms
or its pharmaceutically acceptable salts thereof;
is more than 60% of the total of atropisomers in the referred pharmaceutical composition.

### Claim 4 (depends on 1)

The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.

### Claim 5 (depends on 1)

A process for preparing the pharmaceutical composition, described in claim 1, comprising isolating a the mixture of chlorin or bacteriochlorin atropisomers of formulae:
wherein:
represents a carbon-carbon single bond or a carbon-carbon double bond;
the bold lines indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist above the plane defined by the macrocycle ring;
X2, X4, X6 and X8 are halogen (F, Cl, Br);
X1, X3, X5 and X7 are halogens (F, Cl, Br) or hydrogen;
R1, R2, R3 and R4 are independently —OH, —OR or —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR or —NR2, where R are alkyl of 1 to 12 carbon atoms or R2 represents cycloalkyl with 2 to 12 carbon atoms; and
R5, R6, R7 and R8 are independently H, —OH, —OR, —Cl, or —NHR where R are alkyl of 1 to 12 carbon atoms; and
at least partially, separating by selective precipitation, chromatography, solvent extraction, thermal or photochemical rotational isomerization or selective photodecomposition the atropisomers with most of the groups R1, R2, R3 or R4 on the same side of the macrocycle plane.

### Claim 6 (depends on 5)

The process according to claim 5, wherein the selective precipitation of the chlorin or bacteriochlorin atropisomers is achieved by first dissolving the atropisomer mixture in a solvent of higher polarity and then selectively precipitating the atropisomers of Formula (I-A) and (I-B)
wherein:
represents a carbon-carbon single bond or a carbon-carbon double bond;
the bold lines indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist above the plane defined by the macrocycle ring;
X2, X4, X6 and X8 are halogen (F, Cl, Br);
X1, X3, X5 and X7 are halogens (F, Cl, Br) or hydrogen;
R1, R2, R3 and R4 are independently —OH, —OR or —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR or —NR2, where R are alkyl of 1 to 12 carbon atoms or R2 represents cycloalkyl with 2 to 12 carbon atoms; and
R5, R6, R7 and R8 are independently H, —OH, —OR, —Cl, or —NHR where R are alkyl of 1 to 12 carbon atoms,
by the addition of a solvent with lower polarity to the solution, which leaves the solution enriched in the atropisomers Formula (I-C) and (I-D)
wherein:
represents a carbon-carbon single bond or a carbon-carbon double bond;
the bold lines indicate that the bolded atoms, and the groups attached thereto, are sterically restricted so as to exist above the plane defined by the macrocycle ring;
X2, X4, X6 and X8 are halogen (F, Cl, Br);
X1, X3, X5 and X7 are halogens (F, Cl, Br) or hydrogen;
R1, R2, R3 and R4 are independently —OH, —OR or —SO2R″, where R″ are each independently chosen from —Cl, —OH, -aminoacid, —OR, —NHR or —NR2, where R are alkyl of 1 to 12 carbon atoms or R2 represents cycloalkyl with 2 to 12 carbon atoms; and
R5, R6, R7 and R8 are independently H, —OH, —OR, —Cl, or —NHR where R are alkyl of 1 to 12 carbon atoms,
wherein the sum of the concentrations of the atropisomers Formula (I-C) and (I-D) in the solution adds to at least 70% of the concentration of all atropisomers present in solution.

### Claim 7 (depends on 5)

The process according to claim 5, wherein the solvent extraction comprises a first step of dissolving the chlorin or bacteriochlorin atropisomers mixture with a polar solvent; and a second step with the addition of a less polar solvent that forms a liquid-liquid phase separation with the polar solvent thus extracting the least polar atropisomers.

### Claim 8 (depends on 5)

The process according to claim 5, wherein the recrystallization comprises the formation of crystals containing the atropisomers with most of the groups R1, R2, R3 or R4 on the same side of the macrocycle plane that is complementary to the atropisomer composition in the mother liquor.

### Claim 9 (depends on 5)

The process according to claim 5, wherein the thermal or photochemical rotational isomerization comprises a first step of binding at least one atropisomer of the chlorin or bacteriochlorin atropisomers mixture to a support to which said at least one atropisomer has high affinity; and a second step of providing enough thermal or radiative energy to promote the rotational isomerization of the atropisomers less bound to the support.

### Claim 10 (depends on 5)

The process according to claim 5, wherein the support is silica gel and the atropisomer bounded to the support is the atropisomer with the formulae:

### Claim 11 (depends on 5)

The process according to claim 5, wherein the selective photodecomposition comprises a first step of dissolving the chlorin or bacteriochlorin atropisomers mixture in an aerated solvent; and a second step of irradiating with light that is absorbed by the atropisomer mixture to photodecompose to a greater extent the less photostable atropisomers.

### Claim 12

(canceled)

### Claim 13

(canceled)

### Claim 14 (depends on 1)

A kit comprising a pharmaceutical composition described in claim 1 and instructions for photodynamic therapy/administration of the composition to a subject.

### Claim 15 (depends on 3)

The process according to claim 3, wherein the relative amounts of the atropisomer of the Formula III-C is more than 70% of the total atropisomers in the referred pharmaceutical composition.

### Claim 16 (depends on 3)

The process according to claim 3, wherein the relative amounts of the atropisomer of the Formula III-C is more than 80% of the total atropisomers in the referred pharmaceutical composition.

### Claim 17 (depends on 3)

The process according to claim 3, wherein the relative amounts of the atropisomer of the Formula III-C is more than 90% or 95% of the total atropisomers in the referred pharmaceutical composition.

### Claim 18 (depends on 6)

The process according to claim 6, wherein the sum of the concentrations of the atropisomers Formula (I-C) and (I-D) in the solution adds more than 70% of the total atropisomers in the referred pharmaceutical composition.

### Claim 19 (depends on 6)

The process according to claim 6, wherein the sum of the concentrations of the atropisomers Formula (I-C) and (I-D) in the solution adds more than 80% of the total atropisomers in the referred pharmaceutical composition.

### Claim 20 (depends on 6)

The process according to claim 6, wherein the sum of the concentrations of the atropisomers Formula (I-C) and (I-D) in the solution adds more than 90% of the total atropisomers in the referred pharmaceutical composition.