# US 2021/0330792 A1 · (bacterio)chlorophyll photosensitizers for treatment of eye diseases and disorders

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- Number: US 2021/0330792 A1
- Document ID: US20210330792A1
- Status: Published application
- Kind: A1
- Application number: 17/370,743
- Filed: 2021-07-08
- Published: 2021-10-28
- Earliest claimed: 2011-08-23
- Assignees: Yeda Research and Development Co. Ltd.
- Applicants: Yeda Research and Development Co. Ltd.
- Inventors: Avigdor SCHERZ; Yoram SALOMON; Arie MARCOVICH; Alexander BRANDIS; Daniel WAGNER
- Web page: https://patentgrep.com/patent/US20210330792A1

## 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 9/0048: {Eye, e.g. artificial tears}
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61N 5/062: {Photodynamic therapy, i.e. excitation of an agent}
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/10: for accommodation disorders, e.g. myopia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61N 2005/0659: {infrared}
- 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

## Abstract

An ophthalmic composition is provided, comprising chlorophyll or bacteriochlorophyll compounds for photodynamic treatment (PDT) of diseases, disorders and conditions associated with corneal or scleral anomalies, such as corneal thinning and scleral stretching.

## Claims

### Claim 1

A chlorophyll or bacteriochlorophyll compound for use in photodynamic therapy (PDT) of diseases, disorders and conditions associated with corneal or scleral anomaly.

### Claim 2 (depends on 1)

The chlorophyll or bacteriochlorophyll according to claim 1, wherein said corneal or scleral anomaly is corneal thinning and scleral weakening.

### Claim 3 (depends on 1, 2)

The chlorophyll or bacteriochlorophyll compound method according to claim 1 or 2, which is a derivative of chlorophyll or bacteriochlorophyll having the formula I, II or III:
wherein
M represents 2H or an atom selected from the group consisting of Mg, Pd, Pt, Zn, In, Gd and Yb;
X is O orN—R7;
R1, R′2 and R6 each independently is Y—R8, —NR9R′9 or —N+RRR′9R″9A−;
Y is O or S;
R2 is H, OH or COOR9;
R3 is H, OH, C1-C12 alkyl or C1-C12 alkoxy;
R4 is —CH═CR9R′9, —CH═CR9Hal, —CH═CH—CH2-NR9R′9, —CH═CH—CH2—N+R9R′9R′9 A−, —CHO, —CH═NR9, —CH═N+R9R′9A−, 13 CH2—OR9, —CH2—SR9, —CH2-Hal, —CH2—R9, —CH2—NR9R′9, —CH2—N+R9R′9R″9A−, —CH2—CH2R9, —CH2—CH2Hal, —CH2—CH2OR9, —CH2—CH2SR9, —CH2—CH2—NR9R′9, —CH2—CH2—N+R9R′9R″9A−, —COCH3, C(CH3)═CR9R′9, —C(CH3)═C9Hal, —C(CH3)═NR9, —CH(CH3)═N+R9R′9A−, —CH(CH3)-Hal, —CH(CH3)—OR9, —CH(CH3)—SR9, —CH(CH3)—NR9R′9, —CH(CH3)—N+R9R′9R″9A−, or —C≡CR9;
R′4 is methyl or formyl;
R5 is O, S, N—R9, N+R9R′9A−, CR9R′9, or CR9-Hal;
R7, R8, R9, R′9 and R″9 each independently is:
(a) H.
(b) C1-C25 hydrocarbyl;
(c) C1-C25 hydrocarbyl substituted by one or more functional groups selected from the group consisting of halogen, nitro, oxo, OR, SR, epoxy, epithio, —CONRR′, —COR, COOR″, —OSO3R, —SO3R″, —SO2R, —NHSO2R, —SO2NRR′, —NRR′, ═N—OR, ═N—NRR′, —C(═NR)—NRR′, —NR—NRR′, —(R)N—C(═NR)—NRR′, O←NR—, >C═NR, —(CH2)n—NR—COR′, —(CH2)n—CO—NRR′, —O—(CH2)n—OR, —o—(CH2)n—O—(CH2)n—R, —PRR′, —OPO3RR′, —PO2HR and —PO3R″R″, wherein n is an integer of 1 to 10 and R and R′ each independently is H, hydrocarbyl or heterocyclyl, or R and R′ together with the N atom to which they are attached form a 3-7 membered saturated ring optionally containing a further heteroatom selected from O, S and N, wherein the further N atom may be substituted, and R″ is H, a cation, hydrocarbyl or heterocyclyl;
(d) C1-C25 hydrocarbyl substituted by one or more functional groups selected from the group consisting of positively charged groups, negatively charged groups, basic groups that are converted to positively charged groups under physiological conditions, and acidic groups that are converted to negatively charged groups under physiological conditions;
(e) C1-C25 hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties;
(f) C1-C25 hydrocarbyl containing one or more heteroatoms and/or one or more carbocyclic or heterocyclic moieties and substituted by one or more functional groups as defined in (c) and (d) above:
(g) C1-C25 hydrocarbyl substituted by a residue of an ammo acid, a peptide, a protein, a monosaccharide, an oligosaccharide, or a polysaccharide; or
(h) a residue of an amino acid, a peptide, a protein, a monosaccharide, an oligosaccharide, or a polysaccharide;
R7 may further be —NRR′, wherein R and R′ each is H or C1-C25 hydrocarbyl, optionally substituted by a negatively charged group, preferably SO3−;
R8 may further be H+ or a cation R+10 when R1, R′2 and R6 each independently is Y—R8 ;
R+10 is a metal cation, an ammonium group or an organic cation;
A− is a physiologically acceptable anion;
m is 0 or 1;
the dotted line at positions 7-8 represents an optional double bond; or
pharmaceutically acceptable salts and optical isomers thereof.

### Claim 4 (depends on 3)

The chlorophyll or bacteriochlorophyll compound according to claim 3, wherein the dotted line at positions 7-8 represents a double bond and the compound is a chlorophyll derivative of the formula I, II or III.

### Claim 5 (depends on 3)

The chlorophyll or bacteriochlorophyll compound according to claim 3, wherein the dotted line at positions 7-8 is absent and the compound is a bacteriochlorophyll derivative of the formula I, II or III.

### Claim 6 (depends on 4, 5)

The chlorophyll or bacteriochlorophyll compound according to claim 4 or 5, containing at least one group selected from:
(a) a negatively charged group selected from COO−, COS−, SO3−, or PO32−;
(b) an acidic group that is converted to a negatively charged group at the physiological pH. selected from COOH, COSH, SO3H, or PO3H2, or a salt thereof;
(c) a positively charged group, preferably an end group or a group located within an alkyl chain, selected from; (i) an onium group not containing a N atom such as —O+(RR′), —S+(RR′), —Se+(RR′), —Te+(RR′), —P+(RR′R″), —As+(RR′R″), —Sb+(RR′R″), and —Bi+(RR′R″); (ii) a cation derived from a N-containing group selected from —N+(RR′R″), —(R)N—N+(RR′R″), O←N+(RR′R″)—, >C═N+(RR′), —C(═NR)—N+RR′R″ or —(R)N—C(═NR)—N+RR′R″ group, preferably N+(RR′R″); or (iii) a cation derived from a heteroaromatic compound containing one or more N atoms and optionally O or S atoms such as -pyrazolium, imidazolium, oxazolium, thiazolium, pyridinum, qiunolinium, isoquinolinium, pyrimidinium, 1,2,4-triazinium, 1,3,5-triazinium or purinium; or
(d) a basic group that is converted to a positively charged group under physiological conditions, said basic group is an end group or a group located within an alkyl chain, selected from —NRR′, —C(═NR)—NR′R″, —NR—NR′R″, —(R)N—C(═NR)—NR′R″, O←NRR′—, or >O═NR, or the basic group is a N-containing heteroaromatic radical selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, quinolinyl, isoquinolinyl, pyrimidyl, 1,2,4-triazinyl, 1,3,5-triazinyl or purinyl,
wherein R, R′ and R″ each independently is H. optionally substituted hydrocarbyl or heterocyclyl, or two of R, R′ and R″ together with the N atom to which they are attached form a 3-7 membered saturated ring, optionally containing one or more heteroatoms selected from O, S or N, and optionally further substituted at the additional N atom, said ring is selected from the group consisting of aziridine, pyrrolidine, piperidine, morpholine, thiomorpholine, azepine or piperazine optionally substituted at the additional N atom by C1-C6 alkyl optionally substituted by halo, hydroxyl or amino.

### Claim 7 (depends on 6)

The chlorophyll or bacteriochlorophyll compound-according to claim 6, wherein the compound is a chlorophyll or bacteriochlorophyll of formula II and R6 is —NR9R′9 wherein R9 is H and R′9 is a C1-C10 alkyl substituted by al least one group selected from: a positively charged group, a negatively charged group, an acidic group that is converted to a negatively charged group under physiological conditions, preferably SO3H or an alkaline salt thereof, or a basic group that is converted to a positively charged group under physiological conditions, preferably —NRR′ or —NH—(CH2)2-6—NRR′, wherein each of R and R′ independently is H. C1-C6 alkyl optionally substituted by NH2, or R and R′ together with the N atom form a 5-6 membered saturated ring, optionally containing an O or N atom and optionally further substituted at the additional N atom by —(CH2)2-6—NH2.

### Claim 8 (depends on 7)

The chlorophyll or bacteriochlorophyll compound-according to claim 7, wherein the compound is a bacteriochlorophyll of formula II, wherein:
M is 2H, Mg, Pd, or Zn, preferably 2H or Pd, more preferably Pd;
R1 is selected from:
(i) —O−R10+;
(ii) Y—R8, wherein Y is O or S and R8 is the residue of an amino acid, a peptide or a protein;
(iii) —NH—CH2—CH(OH)—CH2OH;
(iv) —NH—(CCH2)n—OH;
(v) —NH—CH(OH)—CH3;
(vi) —NH—(CH2)n—NR—(CH2)n—OH;
(vii) glycosylamino; or
(viii) NHR′9 which is as defined for R6;
R′2 is C1-C6 alkoxy such as methoxy, ethoxy, propoxy or butoxy, more preferably methoxy;
R4 is —C(═O)—CH3, —CH═N—(CH2)n—SO3−R10+; —CH═N—(CH2)n—COO−R10+; —CH═N—(CH2)n—PO32−(R10+)2; —CH2—NH—(CH2)n—SO3−R10+; —NH—(CH2)n—COO−R10+; —NH—(CH2)n—PO32−(R10+)2; or—C(CH3)═NR9, preferably C(CH3)═N—(CH2)n—NH2, or —C(CH3)═N—(CH2)n—N(R)3+A−;
R6 is selected from (i) NHR′9, selected from:
(a) —NH—(CH2)m—SO3−R10+, preferably —NH—(CH2)2—SO3R10+ or —NH—(CH2)3—SO3R10+;
(b) —NH—(CH2)n—COO−R10+;
(c) —NH—(CH2)n—PO32−(R10+)2;
(d) —NH—(CH2)n—B;
preferably —NH—(CH2)2-1-morpholino or —NH—(CH2)3-piperazino;
(h) —NH—(CH2)n—N(R″)—(CH2)n—NRR′, preferably —NH—(CH2)3—NH—(CH2)3—NH2;
(j) —NH—(CH2)n—NRR′, preferably —NH—CH2—CH2—NRR′;
R10+ is H+, or a monovalent cation such as K+, Na+, Li+, or NH4+ more preferably K+;
X is O, S or NH;
B is a positively charged group selected from ammonium —N+RR′R″, preferably —N(CH3)3+A−,-guanidinium, sulfonium, phosphonium, arsonium; or B is a basic group that is converted to a positively charged group under physiological conditions, selected from amino —NRR′, preferably —NH2, guanidino, phosphino, or arsino;
m is 1 n is an integer from 1 to 10, preferably 2 or 3; and
A− is a physiologically acceptable anion;
wherein R, R′ and R″ each independently is H or C1-C6 alkyl.

### Claim 9 (depends on 8)

The chlorophyll or bacteriochlorophyll compound according to claim 8, wherein the compound is a bacteriochlorophyll of formula II selected from the pharmaceutically acceptable salt with a monovalent or divalent alkaline or alkaline earth metal cation, or with NH4+, of the following compounds:
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2-sulfoethyl) amide;
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 1311-(2-sulfopropyl)amide;
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 171-di-(2-sulfoethyl)amide;
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173-di-(3-sulfopropyl)amide;
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2-sulfoethyl)amide;
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2-sulfopropyl)amide:
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173-di-(2-sulfoethyl)amide; and
31oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173-di-(3-sulfopropyl)amide.

### Claim 10 (depends on 8)

The compound according to claim 8 selected from consisting of:
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2sulfoethyl)amide dipotassium salt (herein WST11);
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2-sulfopropyl)amide dipotassium salt (herein compound 1);
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173-di-(2-sulfoethyl)amide dipotassium salt (herein compound 2); and
Palladium 31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173di-(3-sulfopropyl)amide dipotassium salt (herein compound 3).
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2-sulfoethyl)amide dipotassium salt;
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131-(2-sulfopropyl)amide dipotassium salt;
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173-di-(2-sulfoethyl)amide dipotassium salt; and
31-oxo-15-methoxycarbonylmethyl-rhodobacteriochlorin 131, 173-di-(3-sulfopropyl)amide dipotassium salt.

### Claim 11 (depends on 3)

The chlorophyll or bacteriochlorophyll compound according to claim 3, wherein the compound is a bacteriochlorophyll of the formula I, wherein:
M is Pd;
R1 is OR10+, —NH—(CH2)n—SO3−R10+, —NH—(CH2)n—COO−R10+; or —NH—(CH2)n—PO32− (R10+)2;
R2 is COOCH3;
R3 is H;
R4 is —C(═O)—CH3;
R5 is O;
R10+ is a monovalent cation such as K+, Na+, Li+, or NH4+; and
n is an integer from 1 to 10, preferably 2 or 3.

### Claim 12 (depends on 11)

The chlorophyll or bacteriochlorophyll compound according to claim 11, wherein the compound is palladium bacteriopheophorbide or a pharmaceutically acceptable salt of palladium bacteriopheophorbide a 173-(3-sulfopropyl)amide with a monovalent alkaline or alkaline earth metal cation, or with NH4+, preferably the potassium salt thereof.

### Claim 13 (depends on 3)

The chlorophyll or bacteriochlorophyll compound according to claim 3, wherein the compound is a chlorophyll or bacteriochlorophyll of the formula III, X is —NR7, R7 is —NRR′, R is H and R′ is C2-C6 alkyl substituted by SO3− or an alkaline salt thereof, preferably R7 is—NH—(CH2)3—SO3−R10+, wherein R+10 is a metal cation, an ammonium group or an organic cation, preferably K+.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a chlorophyll or bacteriochlorophyll compound according to any one of claims 1 to 13 for photodynamic therapy (PDT) of diseases, disorders and conditions associated with corneal or scleral anomaly.

### Claim 15 (depends on 14)

The pharmaceutical composition according to claim 14, wherein said corneal or scleral anomaly is corneal thinning and scleral stretching.

### Claim 16 (depends on 14, 35)

The pharmaceutical composition according claim 14 or 35, further comprising a viscous agent for enhancing the viscosity of the formulation and restricting penetration of the chlorophyll or bacteriochlorophyll compound into the cornea.

### Claim 17 (depends on 16)

The pharmaceutical composition according to claim 16, wherein said viscous agent is a polymer, preferably a biopolymer.

### Claim 18 (depends on 17)

The pharmaceutical composition according to claim 17, wherein said is a polysaccharide selected from dextran, scleroglucan and derivatives thereof, Gellan gum. Guar gum or-methylcellulose.

### Claim 19 (depends on 14, 35)

The pharmaceutical composition according claim 14 or 35, further comprising a transepitheliai permeability enhancer for enhancing the penetration of the chlorophyll or bacteriochlorophyll compound through the epithelium.

### Claim 20 (depends on 14, 15, 16, 17, 18, 19)

The pharmaceutical composition according to any one of claims 14 to 19, for topical application.

### Claim 21

The pharmaceutical composition according to any one of clams 14-20, for use in the photodynamic therapy before local irradiation of the eye with fight at a red or near infrared (NIR) wavelength.

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

A method for photodynamic therapy of corneal thinning comprising the steps of:
(a) administering to an individual afflicted with corneal thinning chlorophyll or bacteriochlorophyll compound according to any one of claims 1 to 13, or a pharmaceutical composition according to any one of claims 14 to 22; and (b) irradiating the eye with light at a red or near infrared (NIR) wavelength.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

A method for photodynamic therapy of scleral stretching comprising the steps of:
(a) administering to an individual afflicted with scleral stretching a chlorophyll or bacteriochlorophyll compound according to any one of claims 1 to 13, or a pharmaceutical composition according to any one of claims 14 to 22; and (b) irradiating the eye of with light at a red or near infrared (NIR) wavelength.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 22, 34)

A method for preventing a corneal and/or scleral disease or weakening before, during or after interventional procedures, comprising the steps of: (a) administering to an individual expected to be afflicted with corneal and/or scleral disease or weakening, a chlorophyll or bacteriochlorophyll compound according to any one of claims 1 to 13, or a pharmaceutical composition according to any one of claims 34 to 22; and (b) irradiating the eye with light at a red or near infrared (NIR) wavelength.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)

The chlorophyll or bacteriochlorophyll compound according to any one of claims 1 to 13, the pharmaceutical composition according to any one of claims 14 to 21, or the method according to any one of claims 22 to 24, wherein said diseases, disorders and conditions associated with corneal or scleral anomaly are selected from keratoconus, post-laser-assisted in situ keratomileusis (LASIK) ectasia, post-photorefractive keratectomy (PRK) ectasia, post-infection ectasia, peripheral ectasia, rheumatoid condition of the cornea, degenerative myopia, regular myopia, scleral staphyloma, ocular hypertension glaucoma, low tension glaucoma and combinations thereof.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)

The chlorophyll or bacteriochlorophyll compound according to any one of claims 1 to 13, the pharmaceutical composition according to any one of claims 14 to 21, or the method according to any one of claims 22. to 24, wherein said scleral weakening diseases, disorders and conditions are selected from myopia, macular distortion, atrophy or visual loss.