# US 10,441,666 B2 · Tricarbocyanine-cyclodextrin(s) conjugates and use thereof

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- Number: US 10,441,666 B2
- Document ID: US10441666B2
- Status: Granted
- Kind: B2
- Application number: 14/713,459
- Filed: 2015-05-15
- Published: 2015-11-19
- Granted: 2019-10-15
- Earliest claimed: 2014-05-16
- Assignees: CYANAGEN S.r.l.
- Applicants: Cyanagen S.R.L.
- Inventors: Leopoldo Della Ciana; Norbert Gretz; Rossana Perciaccante; Federica Rodeghiero; Stefania Geraci; Jiaguo Huang; Zeneida Herrera Pérez; Johannes Pill; Stefanie Weinfurter
- Web page: https://patentgrep.com/patent/US10441666B2

## CPC

- A61K 49/0032: {Methine dyes, e.g. cyanine dyes}
- A61K 49/0004: {Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions}
- A61K 49/0054: {Macromolecular compounds, i.e. oligomers, polymers, dendrimers}
- C08B 37/0012: {Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof}
- C08L 5/16: Cyclodextrin; Derivatives thereof
- C09B 69/105: {containing a methine or polymethine dye}
- A61K 49/0017: {Fluorescence in vivo}
- 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)
- C08B: POLYSACCHARIDES; DERIVATIVES THEREOF (polysaccharides containing less than six saccharide radicals attached to each other by glycosidic linkages C07H; fermentation or enzyme-using processes C12P19/00; sugar industry C13; production of cellulose D21)
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)
- 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

The present invention relates to novel tricarbocyanine-cyclodextrin(s) conjugates useful as markers in the diagnosis of kidney diseases, a diagnostic composition comprising said conjugates, their use and their production.

## Claims

### Claim 1

A fluorescent compound of formula (I)
F-Ln-CDn (I)
wherein
F is a tricarbocyanine residue of formula (II)
wherein
R1 and R2 are independently selected from H, SO3H, CO2H, SO2NH2, CH2COOH, NH2, NHCOCH2I, NO2, Br, Cl, CH3;
R3 and R4 are independently selected from C1-4 alkyl, (CH2)3C≡CH, (CH2)4C≡CH (CH2)5COOH, (CH2)3SO3H, (CH2)4SO3H, (CH2)3NH2, (CH2)4NH2, (CH2)3N+(CH3)3, (CH2)5N+(CH3)3, (CH2)3N3, (CH2)4N3, (CH2)3NHCOCH2I, (CH2)4NHCOCH2I, (CH2CH2O)2CH3, (CH2CH2O)3CH3,(CH2CH2O)4CH3;
R5, is selected from
wherein
CD is a cyclodextrin residue of formula (III)
wherein
m is and integer equal to 6, 7 or 8,
R′, R″, R′″ are independently selected from OH, OCH3, OCH2CH3, OCH2CHOHCH3, OCHOHCH3, OCH2COOH, O(CH2)4SO3H, N3, NH2, NHCOCH3, OCH2C≡CH, SH;
L is a linker group resulting from the coupling of the tricarbocyanine of formula (II) to the cyclodextrin(s) of formula (III) according to the following Table:
Functional group of
Functional group
the tricarbocyanine
of the cyclodextrin
(F) in any
(CD) in any
of the groups
of the groups
R3, R4 or R5
R′, R″ or R′′′
Linker group (L)
COOH
OH
—C(O)O—
COOH
NH2
—C(O)NH—
NH2
COOH
—NHC(O)—
NHCOCH2I
SH
NHC(O)CH2S—
C≡CH
N3
N3
C≡CH
n is an integer from 1 to 4,
and salts thereof.

### Claim 2 (depends on 1)

A fluorescent compound according to claim 1, wherein m is equal to 7 or 8.

### Claim 3 (depends on 1)

A fluorescent compound according to claim 1, wherein at least one of the R′, R″, R′″ groups is selected from OCH3, OCH2CH3, OCH2CHOHCH3, with the provision that at least one group from R′, R″, R′″ is OH.

### Claim 4 (depends on 1)

A fluorescent compound according to claim 1, wherein R′ and R″ are OH, and R′″ is selected from OCH3, OCH2CH3, OCH2CHOHCH3, wherein the substitution degree of R′″ is comprised between 0.5 and 1.5 for each unit of Formula (III).

### Claim 5 (depends on 1)

A fluorescent compound according to claim 1, wherein R1 and R2 are independently selected from H, SO3H and COOH.

### Claim 6 (depends on 1)

A fluorescent compound according to claim 1, wherein R3 and R4 are independently selected from methyl, ethyl, (CH2)5COOH, (CH2)4SO3H, (CH2)3N+(CH3)3.

### Claim 7 (depends on 1)

A fluorescent compound according to claim 1, wherein L is selected from an ester, an ether, an amide or

### Claim 8 (depends on 1)

A fluorescent compound according to claim 1 selected from:
a compound of formula (XII):
wherein CD1 and CD2 are, independently, 2-hydroxypropyl-β-cyclodextrin (HβCD) or 2-hydroxypropyl-γ-cyclodextrin (HγCD) and linkers are ester bonds formed in the coupling reaction of a carboxyl group of the tricarbocyanine with a residue group R′″═OH of CD1 and CD2, respectively.

### Claim 9 (depends on 1)

A fluorescent compound according to claim 1 for use in the diagnosis of kidney function in a mammal.

### Claim 10 (depends on 1)

A diagnostic formulation for use in the diagnosis of kidney function, comprising at least one fluorescent compound according to claim 1.

### Claim 11 (depends on 1)

A method for diagnosing kidney function of a mammal, comprising:
(a) administering to the mammal at least one fluorescent compound according to claim 1, and
(b) detecting and measuring the fluorescence emission of the at least one fluorescent compound.

### Claim 12 (depends on 11)

A method according to claim 11, wherein the administration is intravenous.

### Claim 13 (depends on 11)

A method according to claim 11, wherein the fluorescence detection and measurement comprise the detection and measurement of fluorescence emerging from the mammalian skin in response to excitation with a red light or near infrared light source.

### Claim 14 (depends on 11)

The method according to claim 11 wherein fluorescence is detected and measured by placing a sensor device onto the mammalian skin.

### Claim 15 (depends on 11)

The method according to claim 11, wherein the method is carried out over a clinically relevant measuring time.

### Claim 16 (depends on 4)

The fluorescent compound according to claim 4, wherein R′″ is OCH2CHOHCH3.

### Claim 17 (depends on 9)

The fluorescent compound according to claim 9 for use in determining the glomerular filtration rate (GFR).

### Claim 18

A fluorescent compound of formula (I)
F-Ln-CDn (I)
wherein
F is a tricarbocyanine residue of formula (II)
wherein
R1 and R2 are independently selected from H, SO3H, CO2H, SO2NH2, CH2COOH, NH2, NHCOCH2I, NO2, Br, Cl, CH3;
R3 and R4 are independently selected from C1-4 alkyl, (CH2)3C≡CH, (CH2)4C≡CH (CH2)5COOH, (CH2)3SO3H, (CH2)4SO3H, (CH2)3NH2, (CH2)4NH2, (CH2)3N+(CH3)3, (CH2)5N+(CH3)3, (CH2)3N3, (CH2)4N3, (CH2)3NHCOCH2I, (CH2)4NHCOCH2I, (CH2CH2O)2CH3, (CH2CH2O)3CH3, (CH2CH2O)4CH3;
R5 is selected from
wherein
CD is a cyclodextrin residue of formula (III)
wherein
m is and integer equal to 6, 7 or 8,
R′, R″, R′″ are independently selected from OH, OCH3, OCH2CH3, OCH2CHOHCH3, OCHOHCH3, OCH2COOH, O(CH2)4SO3H, N3, NH2, NHCOCH3, OCH2C≡CH, SH;
L is a linker group resulting from the coupling of the tricarbocyanine of formula (II) to the cyclodextrin(s) of formula (III) according to the following Table:
Functional group of
Functional group
the tricarbocyanine
of the cyclodextrin
(F) in any of the
(CD) in any of the
groups R3, R4 or R5
groups R′, R″ or R′′′
Linker group (L)
COOH
OH
—C(O)O—
COOH
NH2
—C(O)NH—
NH2
COOH
—NHC(O)—
NHCOCH2I
SH
NHC(O)CH2S—
C≡CH
N3
N3
C≡CH
n is an integer from 1 to 4,
and salts thereof, and
wherein the fluorescent compound is a compound of formula (XII):
wherein CD1 and CD2 are, independently, 2-hydroxypropyl-β-cyclodextrin (HβCD) or 2-hydroxypropyl-γ-cyclodextrin (HγCD) and the linkers L of Formula (I) are ester bonds formed in the coupling reaction of a carboxyl group of the tricarbocyanine with a residue group R′″═OH of CD1 and CD2, respectively.