# US 10,501,630 B2 · Rhodamine dyes and conjugates

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- Number: US 10,501,630 B2
- Document ID: US10501630B2
- Status: Granted
- Kind: B2
- Application number: 15/948,338
- Filed: 2018-04-09
- Published: 2019-01-17
- Granted: 2019-12-10
- Earliest claimed: 2010-04-02
- Assignees: Pharmacophotonics, Inc.
- Applicants: Pharmacophotonics, Inc.
- Inventors: Ulf J. Bremberg; Erik Ringberg; Wei Berts; Anthony De Belder; James S. Strickland
- Web page: https://patentgrep.com/patent/US10501630B2

## CPC

- C09B 11/24: Phthaleins containing amino groups {; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes}
- A61K 49/0041: {Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal (in vivo G01N)}
- A61K 49/0054: {Macromolecular compounds, i.e. oligomers, polymers, dendrimers}
- C09B 5/00: Dyes with an anthracene nucleus condensed with one or more heterocyclic rings with or without carbocyclic rings
- 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)
- 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)

## Abstract

The present invention relates generally to novel rhodamine dyes which upon conjugation with another molecule form single isomeric conjugation products. These novel rhodamine dyes contain only one single functional group on the rhodomine molecule for conjugation so that their conjugation products are single isomeric conjugation products.

## Claims

### Claim 1

A compound comprising a rhodamine dye or a salt thereof having the general structure of
wherein:
R5 is independently H,
R4 is independently H,
R3 is independently H,
R2 is independently H or
and R1 is H, provided that only one of R2, R3, R4 and R5 is not H,
wherein the rhodamine dye is capable of conjugating with another molecule via the functional group; and wherein the Ar on one or more of the substituents is an aryl group and the R6 or R7 on the substituents form a spacer which contains a single functional group on either R6 or R7 suitable for conjugation with another molecule.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the salt is a pharmaceutically acceptable salt.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the salt is selected from the group consisting of trifluoroacetate, chloride, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, fortmate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.

### Claim 4 (depends on 3)

The compound of claim 3, wherein the salt is trifluoroacetate or chloride.

### Claim 5 (depends on 1)

The compound of claim 1 wherein the functional group is selected from the group consisting of amines, alcohols, isocyanates, isothiocyanates, thiols, and carboxylic acids, or a pharmaceutically acceptable salt therereof.

### Claim 6 (depends on 1)

The compound of claim 1 wherein the spacer is selected from the groups consisting of alkyl, amide, alkyl sulfonamide, alkyl ether, alkyl amine, and alkyl alide, or a pharmaceutically acceptable salt therereof.

### Claim 7 (depends on 6)

The compound of claim 6 wherein the alkyl group has a carbon chain length of 1 to 20, or a pharmaceutically acceptable salt therereof.

### Claim 8 (depends on 1)

The compound of claim 1 wherein R6 and R7 are connected to form a cyclic structure, or a pharmaceutically acceptable salt therereof.

### Claim 9 (depends on 8)

The compound of claim 8 wherein the cyclic structure is
or a pharmaceutically acceptable salt therereof.

### Claim 10 (depends on 1)

The compound of claim 1 wherein R1, R2, R4, and R5 are H, and R3 is
or a pharmaceutically acceptable salt therereof.

### Claim 11 (depends on 10)

The compound of claim 10 undergoing a rearrangemt to form an isomer having the structure of
or a pharmaceutically acceptable salt therereof.

### Claim 12 (depends on 11)

The compound of claim 11 wherein the salt is the dichloride salt.

### Claim 13 (depends on 1)

The compound of claim 1 wherein R1, R2, R4, and R5 are H, and R3 is
or a pharmaceutically acceptable salt therereof.

### Claim 14 (depends on 1)

The compound of claim 1 wherein R1, R2, R4, and R5 are H, and R3 is
or a pharmaceutically acceptable salt therereof.

### Claim 15 (depends on 1)

The compound of claim 1 wherein R1, R2, R4, and R4 are H, and R5 is
and R6 and R7 are each independently H,
or a pharmaceutically acceptable salt therereof.

### Claim 16 (depends on 1)

A process for preparing the compound of claim 1 comprising treating an intermediate with a catalyst.

### Claim 17 (depends on 16)

The process of claim 16 wherein said intermediate is:

### Claim 18 (depends on 16)

The process of claim 16 wherein said intermediate is prepared by reacting a 8-hydroxyjulolidine with a benzoic acid or a derivative thereof or with sodium 2-formylbenzene-1-sulfonate.

### Claim 19 (depends on 18)

The process of claim 18 wherein said benzoic acid or a derivative thereof is selected from the group consisting of 4-formyl benzoic acid, 3-formyl benzoic acid, and 4-bromobenzaldehyde.

### Claim 20 (depends on 16)

The process for preparing the compound of claim 16 wherein the catalyst is 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (DCM).

### Claim 21 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A method for fluorescent imaging using the compound of claim 1.