# US 10,370,362 B2 · Pyrazine derivatives with extended conjugation and methods of using the same in optical applications

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- Number: US 10,370,362 B2
- Document ID: US10370362B2
- Status: Granted
- Kind: B2
- Application number: 14/962,242
- Filed: 2015-12-08
- Published: 2016-03-31
- Granted: 2019-08-06
- Earliest claimed: 2006-06-22
- Assignees: MediBeacon Inc.
- Applicants: MediBeacon Inc.
- Inventors: William L. Neumann; Raghavan Rajagopalan; Richard B. Dorshow
- Web page: https://patentgrep.com/patent/US10370362B2

## CPC

- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- A61K 49/0021: {the fluorescent group being a small organic molecule}
- A61P 13/12: of the kidneys
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 241/24: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 241/26: with nitrogen atoms directly attached to ring carbon atoms
- C07D 241/28: in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 473/18: one oxygen and one nitrogen atom, e.g. guanine
- C07D 473/34: attached in position 6, e.g. adenine
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The present invention relates to pyrazine derivatives capable of absorbing and emanating spectral energy in the visible and/or near infrared spectrum. Pyrazine derivatives of the invention may be administered to a patient in the form of a pharmaceutically acceptable composition and utilized in medical (e.g., diagnostic imaging) procedures.

## Claims

### Claim 1

An optical diagnostic agent having Formula 1
or pharmaceutically acceptable salt thereof, wherein:
X is -Ar-Y, —C(R4)═C(R5)-Ar-Y, —C≡C-Ar-Y, —N═N-Ar-Y, —CO-Ar-Y, —N(R6)-Ar-Y, —O-Ar-Y, —S-Ar-Y, —SO-Ar-Y, —SO2-Ar-Y, —C(R4)═C(R5)—Y, or —C≡C—Y;
Ar is phenyl, naphthyl, biphenyl, pyridyl, pyridazyl, pyrimidinyl, pyrazinyl, pyrrolyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl or thiadiazolyl; with the proviso that if Ar is phenyl, pyrrolyl, or thiopheneyl, then at least one of R1, R2, and R3 is other than hydrogen;
each Y is independently hydrogen, C1-C10 alkyl, halo, haloalkyl, —CN, —CO2R7, —CONR8R9, —COR10, —NO2, —SOR11, —SO2R12, —SO2OR13, —PO3R14R15, —OR16, —SR17, —NR18R19, —N(R20)COR21, —P(R22)3, —CO(AA)j, or —CONH(PS)k;
each of, R1, R2 and R3 is independently hydrogen, C1-C10 alkyl, halo, haloalkyl, —CN, —CO2R7, —CONR8R9, —COR10, —NO2, —SOR11, —SO2R12, —SO2OR13, —PO3R14R15, —OR16, —SR17, —NR18R19, —N(R20)COR21, —P(R22)3, —CO(AA)j, —CONH(PS)k, or X; with the proviso that no more than one of R1, R2 and R3 is a —CN group and at least one of R1, R2 and R3 comprises a substituted or unsubstituted amino group;
(AA)j is a polypeptide chain comprising the same or different amino acids linked together by peptide bonds, wherein j is an integer from 1 to 50;
(PS)k is a sulfated or non-sulfated polysaccharide chain comprising the same or different monosaccharide units connected together by glycosidic linkages, wherein k is an integer from 1 to 50;
each of R4 to R22 is independently —H, C1-C10 alkyl, —(CH2)aOR23, —CH2(CHOH)aR24, —CH2(CHOH)aCO2H, —(CHCO2H)aCO2H, —(CH2)aNR25R26, —CH[(CH2)bNH2]aCO2H, —CH[(CH2)bNH2]aCH2OH, —CH2(CHNH2)aCH2NR27R28, —(CH2CH2O)cR29, or —(CH2)dCO(CH2CH2O)cR30;
each of R23 to R30 is independently —H or —CH3;
each of a, b, and d is independently an integer from 1 to 10; and
c is an integer from 1 to 100.

### Claim 2 (depends on 1)

The optical diagnostic agent of claim 1 wherein X is -Ar-Y, —C(R4)═C(R5)-Ar-Y, —N═N-Ar-Y, —CO-Ar-Y, —N(R6)-Ar-Y, —O-Ar-Y, —S-Ar-Y, —SO-Ar-Y, or —SO2-Ar-Y.

### Claim 3 (depends on 1)

The optical diagnostic agent of claim 1 wherein X is -Ar-Y.

### Claim 4 (depends on 1)

The optical diagnostic agent of claim 1 wherein X is —C(R4)═C(R5)-Ar-Y.

### Claim 5 (depends on 1)

The optical diagnostic agent of claim 1 wherein X is —N═N-Ar-Y.

### Claim 6 (depends on 1)

The optical diagnostic agent of claim 1 wherein Ar is phenyl, naphthyl, biphenyl, pyridyl, pyrazinyl, pyrrolyl, furanyl, and thiopheneyl.

### Claim 7 (depends on 1)

The optical diagnostic agent of claim 1 wherein Ar is phenyl, pyridyl, pyrazinyl, pyrrolyl, furanyl, or thiopheneyl.

### Claim 8 (depends on 1)

The optical diagnostic agent of claim 1 wherein Ar is phenyl, pyrrolyl, or furanyl.

### Claim 9 (depends on 1)

The optical diagnostic agent of claim 1 wherein Ar is phenyl.

### Claim 10 (depends on 1)

The optical diagnostic agent of claim 1 wherein Ar is pyrrolyl.

### Claim 11 (depends on 1)

The optical diagnostic agent of claim 1 wherein Ar is furanyl.

### Claim 12 (depends on 1)

The optical diagnostic agent of claim 1 wherein Y is —H, C1-C10 alkyl, halo, haloalkyl, —CN, —CO2R7, —CONR8R9, —COR10, —NO2, —SO2R12, —OR16, —SR17, —NR18R19, —N(R20)COR21, —CO(AA)j, or —CONH(PS)k.

### Claim 13 (depends on 1)

The optical diagnostic agent of claim 1 wherein Y is —H, alkyl, halo, haloalkyl, —CN, —CO2R7, —CONR8R9, —OR16, —NR18R19, or —N(R20)COR21.

### Claim 14 (depends on 1)

The optical diagnostic agent of claim 1 wherein Y is —H, —CN, —CO2R7, —CONR8R9, —OR16, —NR18R19, or —N(R20)COR21.

### Claim 15 (depends on 1)

The optical diagnostic agent of claim 1 wherein Y is —H, —CO2R7, —OR16, or NR18R19.

### Claim 16 (depends on 1)

The optical diagnostic agent of claim 1 wherein Y is —H.

### Claim 17 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of R1 to R3 is independently C1-C10 alkyl, —CN, —CO2R7, —CONR8R9, —OR16, —NR18R19, —CO(AA)j, —CONH(PS)k, or X.

### Claim 18 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of R1 to R3 is independently —CN, —CO2R7, —CONR8R9, —NR18R19, or X.

### Claim 19 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of R1 to R3 is independently —CN, —CONR8R9, —NR18R19, or X.

### Claim 20 (depends on 1)

The optical diagnostic agent of claim 1 wherein:
one of R1, R2, and R3 is X; and
each of the other two of R1, R2, and R3 is independently —CN, —CONR8R9, or —NR18R19.

### Claim 21 (depends on 1)

The optical diagnostic agent of claim 1 wherein:
one of R1, R2, and R3 is —CN, —CONR8R9, or —NR18R19; and
each of the other two of R1, R2, and R3 is X.

### Claim 22 (depends on 1)

The optical diagnostic agent of claim 1 wherein:
each of R1 and R3 is independently —OR16, —SR17, or —NR18R19; and
R2 is —CN, —CO2R7, —CONR8R9, —CORm, —SO2R12, —CO(AA)j, —CONH(PS)k, or X.

### Claim 23 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of R4 to R21 is independently —H, C1-C10 alkyl, —(CH2)aOR23, —CH2(CHOH)aR24, —CH2(CHOH)aCO2H, —(CHCO2H)aCO2H, —(CH2)aNR25R26, —CH[(CH2)bNH2]aCO2H, —CH[(CH2)bNH2]aCH2OH, —CH2(CHNH2)aCH2NR27R28, —(CH2CH2O)cR29, or —(CH2)dCO(CH2CH2O)cR30.

### Claim 24 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of R7 to R21 is independently —H, C1-C10 alkyl, or —(CH2)aOR23.

### Claim 25 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of R7 to R21 is independently —H or C1-C10 alkyl.

### Claim 26 (depends on 1)

The optical diagnostic agent of claim 1 wherein (AA)j is a polypeptide chain consisting of amino acids selected from aspartic acid, asparagine, arginine, histidine, lysine, glutamic acid, glutamine, serine, and homoserine.

### Claim 27 (depends on 26)

The optical diagnostic agent of claim 26 wherein j is an integer from 1 to 20.

### Claim 28 (depends on 1)

The optical diagnostic agent of claim 1 wherein (PS)k is a sulfated or non-sulfated polysaccharide chain consisting of glucose, fructose, mannose, and ribose.

### Claim 29 (depends on 28)

The optical diagnostic agent of claim 28 wherein k is an integer from 1 to 20.

### Claim 30 (depends on 1)

The optical diagnostic agent of claim 1 wherein each of a, b, and d is independently an integer from 1 to 6.

### Claim 31 (depends on 1)

The optical diagnostic agent of claim 1 wherein c is an integer from 1 to 20.

### Claim 32 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 33 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 34 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 35 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 36 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 37 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 38 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 39 (depends on 1)

The optical diagnostic agent of claim 1, wherein the optical diagnostic agent is any of formula:

### Claim 40 (depends on 1)

A method of imaging a patient comprising:
administering the optical diagnostic agent of claim 1,
exposing the administered compound to visible and/or near infrared light,
detecting spectral energy emanating from the administered agent, and
generating an image.